Thiazole derivative

ABSTRACT

A thiazole compound of the formula: ##STR1## wherein T is lower alkylene; u is 0 or 1; R 1  and R 2  are the same or different and are each H, or lower alkyl, etc.; R 3  is ##STR2## R 4  is H or lower alkanoyloxy-lower alkyl, which shows inhibitory activity on protein kinase C (PKC, Ca 2+  /phospholipid-depending serine/threonine protein phosphatase), and are useful as a protein kinase C inhibitor.

This application is a 371 of PCT/JP97/02609 filed Jul. 29, 1997.

TECHNICAL FIELD

The present invention relates to a novel thiazole derivative.

BACKGROUND ART

There have hitherto been known various thiazole derivatives, among which some compounds having a somewhat similar substituents to those of the present invention are disclosed in the following literatures.

JP-A-2-306916 discloses inhibitors for platelet adhesion comprising a benzazole compound of the following formula: ##STR3## wherein X is S or >N--R³ (R³ is H, lower alkyl, etc.); R¹ is halogen, cyano, cyano-substituted lower alkoxy, phenyl-alkyl having a substituent on benzene ring, substituted furyl-alkoxy, substituted pyrrolidinyl-alkyl, substituted amino, substituted amino-alkyl or -alkoxy, etc.; R² is pyrrolyl having optionally alkyl substituent, thienyl, pyridylthio-lower alkyl, phenyl group which has optionally 1 to 3 substituents selected from lower alkoxy, lower alkyl, OH, halogen, or --O--Y--NR⁸ R⁹ (Y is lower alkylene, R⁸ and R⁹ are each H, lower alkyl, cycloalkyl, or both combine to form a nitrogen-containing 5- or 6-membered saturated hetero-cyclic group, or --NR¹⁰ R¹¹ (R¹⁰ and R¹¹ are each H, lower alkyl, substituted phenyl, or both combine to form a heterocyclic group). However, the benzazole compounds of this literature are significantly different from the thiazole compounds of the present invention in the substituents at 2-position of the thiazole nucleus. Besides, this literature does not disclose any compounds having protein kinase C inhibitory activities as in the present invention.

European Patent 318 084 (=U.S. Pat. Nos. 4,957,932 and 5,037,840) discloses that the benzoheterazoles of the following formula are leukotriene antagonists and inhibitors of leukotriene biosynthesis and are useful as antiasthmetic, antiallergic, anti-inflammatory and cytoprotective agents. ##STR4## wherein R¹ is H, halogen, alkyl, etc.; R² is alkyl, alkenyl, etc.; R³ is H or R² ; R⁴ is H, halogen, --NO₂, etc.; R⁵ is H, halogen, --NO₂, etc.; R⁷ is H or alkyl; X² and X³ are O, S, S(O), etc.; X⁴ is NR³, O or S; Z¹ and Z² are --CONR³ -- or --HET(--R³,--R⁵)--; and Q¹ and Q² are --COOR³, --CONHS(O)₂ R¹³, --CN, etc. However, these benzoheterazoles of this literature are essentially different from the thiazole compounds of the present invention in the substituent at 2-position of the azole nucleus. Besides, this literature does not disclose any compounds having protein kinase C inhibitory activity.

Some thiazole or benzothiazole compounds having similar chemical structure to the benzoheterazoles of the above European Patent 318084 are also disclosed in PCT publications WO 93/21168 and WO 93/21169 and therein it is mentioned that those compounds are useful as leukotriene antagonist, but these thiazole or benzothiazole compounds of these literatures are clearly different from the thiazole compounds of the present invention in the substituent at 2-position likewise, and further these literatures do not disclose any compound having protein kinase C inhibitory activity, either.

DISCLOSURE OF INVENTION

The thiazole derivatives of the present invention are novel compounds, and have not been disclosed in any literature, and have the following formula (1). ##STR5## wherein T is a lower alkylene; u is 0 or 1;

R¹ and R² are the same or different and are each a hydrogen atom or a lower alkyl, or both combine to form a group: --(CH₂)_(n) -- (n is 4 or 5) or to form a benzene ring which may optionally be substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino having optionally a lower alkyl substituent, or a halogen atom;

R³ is a group of the formula: ##STR6## wherein R^(11b), p, R^(11a) are defined hereinafter; A is a lower alkylene; Z is O or S; s is 0 or 1; m is 1 or 2;

R⁴ is a hydrogen atom or a lower alkanoyloxy-lower alkyl;

R⁵ s are the same or different and are each a member selected from (a) a hydrogen atom, (b) an alkyl having optionally a hydroxy substituent, (c) a halogen atom, (d) a group of the formula: --(O)_(t) --A--(CO)_(l) --NR⁷ R⁸ (wherein t is 0 or 1, A is a lower alkylene, l is 0 or 1, and R⁷ and R⁸ are the same or different and are each a hydrogen atom or a lower alkyl, or both combine together with the nitrogen atom to which they bond to form a 5- to 7-membered saturated heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group being optionally substituted by a member selected from a group of the formula: --(A)_(l) --NR⁹ R¹⁰ (wherein A and l are as defined above, and R⁹ and R¹⁰ are the same or different and are each a hydrogen atom or a lower alkyl, or both combine together with the nitrogen atom to which they bond to form a 5- to 7-membered saturated heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group having optionally a lower alkyl substituent), a lower alkyl having optionally a hydroxy substituent, a hydroxy group, and a lower alkanoyl), (e) a lower alkoxycarbonyl-lower alkyl, (f) a lower alkanoyloxy-lower alkyl, (g) a lower alkoxy having optionally a halogen substituent, (h) a halogen-substituted lower alkyl, (i) a carboxyl-substituted lower alkyl, (j) a lower alkoxycarbonyl, (k) a lower alkenyloxy, (l) a phenyl-lower alkoxy, (m) a cycloalkyloxy, (n) a phenyl, (o) a phenyloxy, (p) a hydroxy, (q) a lower alkylthio, (r) a lower alkenyl, or (s) an amino having optionally a lower alkyl substituent;

R⁶ is a group of the formula:

    --CO--CH═CR.sup.11b --(CO).sub.p --R.sup.11a           (1)

or

    --CO--C.tbd.C--COR.sup.14 ;                                (2)

p is 0 or 1;

R^(11b) is a hydrogen atom or a lower alkyl;

R^(11a) is a hydroxy, a lower alkoxy, or a 5- to 10-membered, monocyclic or dicyclic, saturated or unsaturated heterocyclic group which contains 1 to 4 hetero atoms selected from a nitrogen, oxygen or sulfur atom as a ring member, said heterocyclic group having optionally 1 to 3 substituents selected from the group consisting of (i) a lower alkyl, (ii) a group of the formula: --(B)_(l) --NR¹² R¹³ (wherein 1 is as defined above, B is --CO--A-- (A is as defined above), a carbonyl, or a lower alkylene, and R¹² and R¹³ are the same or different and are each a hydrogen atom, a lower alkyl, or a lower alkyl substituted by an amino having optionally a lower alkyl substituent, or both combine together with the nitrogen atom to which they bond to form a 5- to 12-membered saturated, monocyclic, dicyclic or spirocyclic heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group having optionally a substituent selected from a lower alkyl, a lower alkoxycarbonyl, a lower alkoxy-substituted lower alkyl, an amino having optionally a lower alkyl substituent, and a hydroxy-substituted lower alkyl), (iii) a lower alkoxycarbonyl, (iv) a hydroxy-substituted lower alkyl, (v) a pyridyl being optionally substituted by a lower alkyl having optionally a halogen substituent on the pyridine ring, (vi) a halogen-substituted lower alkyl, (vii) a lower alkoxy, (viii) a cycloalkyl, (ix) a hydroxy, (x) a tetrahydropyranyloxy-substituted lower alkyl, (xi) a pyrimidyl, (xii) a lower alkoxy-substituted lower alkyl, (xiii) a carboxyl, (xiv) a phenyl-lower alkoxy, (xv) a phenyl-lower alkyl having optionally a lower alkylenedioxy on the phenyl ring, (xvi) a lower alkanoyloxy, and (xvii) a piperidinyl having optionally a lower alkyl substituent on the piperidine ring;

R¹⁴ is a hydroxy or a lower alkoxy; and

when m is 1, the groups A and R⁵ may combine to form a group of the formula: ##STR7## (wherein R⁶ is as defined above, and r is 0, 1 or 2), or when m is 2, two R⁵ groups may combine to form a lower alkylenedioxy, a lower alkylene, or a group of the formula: --(CH₂)₂ --CONH--, or the groups R⁵ and R⁶ may combine to form a group of the formula: --CO--CH(R²⁸)--CH(R^(28'))--W-- (wherein R²⁸ and R^(28') are a hydrogen atom or a carboxyl group, provided that both R²⁸ and R²⁸ are not simultaneously a carboxyl group, and W is --N(R^(29a))-- or ##STR8## (wherein R^(29a) is a hydrogen atom or a lower alkyl, R^(29b) is a lower alkyl, and X is a halogen atom)),

or a salt thereof.

The thiazole derivatives of the formula (1) show inhibitory activity on protein kinase C (PKC, Ca²⁺ /phospholipid-depending serine/threonine protein phosphatase), and are useful as a protein kinase C inhibitor.

It has been proved that PKC plays an important role in the regulation of various biological functions such as the metabolism regulation, the cell prolification, the cell differentiation, the release reaction of neurotransmitter,etc. Therefore, it is indicated that a PKC inhibitor may be useful in the prophylaxis or treatment of various diseases caused by the hyperaction of the above-mentioned biological functions being participated by PKC.

More particularly, the protein kinase C inhibitors containing as an active ingredient the present thiazole derivative are useful as an agent for treatment of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, etc., various allergic diseases such as Crohn's disease, colitis ulcerosa, asthma, atopic dermatitis; an agent for protection of rejection in organ transplant, GVHD reaction, etc.; an agent for prophylaxis or treatment of various ischemic diseases in the organs such as heart, liver, kidney, brain, etc., acute pancreatitis, sepsis, multiple organs failure introduced by burn, ARDS, by inhibiting the production of cytokinin derived from T-cell such as IL-2, or inflammatory cytokinin such as TNF-α.

Further, by other biological functions such as cell prolification, hormone secretion, regulation of metabolism, etc. which are concerned with PKC, the protein kinase C inhibitors of the present invention are useful in the prophylaxis or treatment of cancer, diabetes, Alzheimer disease, arteriosclerosis, HIV infection, nephritis, angiitis, etc.

Each group in the above formula (1) specially means the following groups.

The lower alkyl group includes a straight chain or branched chain C₁ -C₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.

The lower alkoxy group includes a straight chain or branched chain C₁ -C₆ alkoxy group, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.

The halogen atom is fluorine atom, chlorine atom, bromine atom or iodine atom.

The lower alkanoyloxy-substituted lower alkyl group includes a straight chain or branched chain C₁ -C₆ alkyl group which is substituted by 1 or 2 straight chain or branched chain C₂ -C₆ alkanoyloxy groups, for example, acetyloxymethyl, 2-propionyloxyethyl, 1-butyryloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl, 6-acetyloxyhexyl, 6-tert-butylcarbonyloxyhexyl, 1,1-dimethyl-2-hexanoyloxyethyl, 2-methyl-3-acetyloxypropyl, diacetyloxymethyl, 1,3-diacetyloxypropyl, etc.

The alkyl group having optionally a hydroxy substituent includes a straight chain or branched chain C₁ -C₈ alkyl group which may optionally have 1 to 3 hydroxy substituents, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 1,3-dihydroxypropyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, 7-hydroxyheptyl, 8-hydroxyoctyl, etc.

The lower alkylene group includes a straight chain or branched chain C₁ -C₆ alkylene group, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, etc.

The 5- to 7-membered saturated heterocyclic group which is formed by combining R⁷ and R⁸, or R⁹ and R¹⁰ together with the adjacent nitrogen atom with or without being intervening with another nitrogen atom or an oxygen atom, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, homopiperazinyl, homomorpholino, etc.

The lower alkyl group having optionally a hydroxy substituent includes, in addition to the above lower alkyl groups, a straight chain or branched chain C₁ -C₆ alkyl group which may optionally have 1 to 3 hydroxy substituents, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, etc.

The lower alkanoyl group includes a straight chain or branched chain C₁ -C₆ alkanoyl group, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, t-butylcarbonyl, hexanoyl, etc.

The above heterocyclic group which is substituted by a group of the formula: --(A)_(l) --NR⁹ N¹⁰ (A is a lower alkylene group, l is 0 or 1, R⁹ an R¹⁰ are the same or different and each are a hydrogen atom or a lower alkyl group, or R⁹ and R¹⁰ combine together with the nitrogen atom to which they bond to form a 5- or 7-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or an oxygen atom, and said heterocyclic group having optionally a lower alkyl substituent), a lower alkyl group having optionally a hydroxy substituent, a hydroxy group and a lower alkanoyl group includes the above mentioned heterocyclic groups having 1 to 3 sustituents selected from a group of the formula: --(A)_(l) --NR⁹ N¹⁰ (A is a straight chain or branched chain C₁ -C₆ alkylene group, l is 0 or 1, R⁹ an R¹⁰ are the same or different and each are a hydrogen atom or a straight chain or branched chain C₁ -C₆ alkyl group, or R⁹ and R¹⁰ combine together with the nitrogen atom to which they bond to form a 5- or 7-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or an oxygen atom, and said heterocyclic group having optionally 1 to 3 straight chain or branched chain C₁ -C₆ alkyl substituents), a straight chain or branched chain alkyl group having optionally 1 to 3 hydroxy substituents, a hydroxy group and a straight chain or branched chain C₁ -C₆ alkanoyl group, for example, 4-methylpiperazinyl, 2-(4-methyl-1-piperazinyl)methylmorpholino, 4-(4-methyl-1-piperazinyl)piperidinyl, 4-methylhomopiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 4-morpholinopiperidinyl, 2-[(1-pyrrolidinyl)methyl]morpholino, 4-hydroxypiperidinyl, 4-acetylpiperazinyl, 4-dimethylaminopiperidinyl, 4-(4-methyl-1-homopiperazinyl)piperidinyl, 4-(4,5-dimethyl-1-homopiperazinyl)piperidinyl, 4-(3-methyl-4-ethyl-1-piperazinyl)piperidnyl, 4-(3-methyl-4-n-propyl-1-piperazinyl)piperidinyl, 4-(3,4-dimethyl-1-piperazinyl)piperidinyl, 4-(4-isopropyl-3-methylpiperazinyl)piperidinyl, 4-(4-methyl-3-isopropylpiperazinyl)piperidinyl, 2-methylpyrrolidinyl, 3-ethylpyrrolidinyl, 2,3-dimethylpyrrolidinyl, 2,3,4-trimethylpyrrolidinyl, 2-propylmorpholino, 3-(1-pyrrolidinyl)pyrrolidinyl, 3-isopropylmorpholino, 2,3-dimethylmorpholino, 4-n-butylpiperidinyl, 3,4,5-trimethylpiperidinyl, 3-pentylpiperidinyl, 4-methylhomopiperazinyl, 4,5-dimethylhomopiperazinyl, 4-hexylhomopiperazinyl, 3-methyl-4-ethylpiperazinyl, 3-methyl-4-n-propyl-1-piperazinyl, 3,4-dimethylpiperazinyl, 4-isopropyl-3-methylpiperazinyl, 4-methyl-3-isopropylpiperazinyl, 4-methylhomomorpholino, 3-propionylpyrrolidinyl, 4-butyrylpiperidinyl, 4-pentanoylpiperazinyl, 3-hexanoylmorpholino, 4-acetylhomopiperazinyl, 3-hydroxymorpholino, 4-hydroxyhomopiperazinyl, 4-hydroxypiperazinyl, 3-hydroxypyrrolidinyl, 3-hydroxymethylpyrrolidinyl, 3-(3-hydroxypropyl)morpholino, 2-hydroxymethylhomomorpholino, 2-(4-methyl-1-piperazinyl)methylhomomorpholino, 4-(1,3-dihydroxy-2-propyl)piperazinyl, 4-ethylhomopiperazinyl, 3-(4-methyl-1-homopiperazinyl)pyrrolidinyl, 4-methyl-3-(1-piperidinyl)methylpiperazinyl, 4-methyl-3-(4-methyl-1-homopiperazinyl)methylpiperazinyl, 4-methyl-3-(4-methyl-1-piperazinyl)methylpiperazinyl, etc.

The above heterocyclic group substituted by a lower alkyl group includes the above heterocyclic groups substituted by 1 to 3 straight chain or branched chain C₁ -C₆ alkyl groups, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 1-methylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-ethylhomopiperazinyl, 4-methylhomopiperazinyl, 4-hexylpiperazinyl, 4-methylhomopiperazinyl, 4,5-dimethylhomopiperazinyl, 3-methyl-4-ethylpiperazinyl, 3-methyl-4-n-propylpiperazinyl, 4-isopropyl-3-methylpiperazinyl, 4-methyl-3-isopropylpiperazinyl, 4-methylhomomorpholino, etc.

The lower alkoxycarbonyl-substituted lower alkyl group includes a straight chain or branched chain C₁ -C₆ alkyl group which is substituted by a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, for example, methoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarbonylmethyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxycarbonylpentyl, 6-propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl, etc.

The lower alkanoyloxy-substituted lower alkyl group includes a straight chain or branched chain C₁ -C₆ alkyl group which is substituted by a straight chain or branched chain C₂ -C₆ alkanoyloxy group, for example, acetyloxymethyl, 2-propionyloxyethyl, 1-butyryloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl, 6-acetyloxyhexyl, 6-tert-butylcarbonyloxyhexyl, 1,1-dimethyl-2-hexanoyloxyethyl, 2-methyl-3-acetyloxypropyl, etc.

The lower alkoxy group having optionally a halogen substituent includes a straight chain or branched chain C₁ -C₆ alkoxy group which optionally has 1 to 3 halogen substituents, for example, in addition to the above lower alkoxy groups, trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2-methylpropoxy, 6-bromohexyloxy, 5,6-dichlorohexyloxy, etc.

The halogen-substituted lower alkyl group includes a straight chain or branched chain C₁ -₆ alkyl group, which has 1 to 3 halogen substituents, for example, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 6-bromohexyl, 5,6-dichlorohexyl, etc.

The carboxy-substituted lower alkyl group includes a carboxyalkyl group wherein the alkyl moiety is a straight chain or branched chain C₁ -C₆ alkyl group, for example, carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl, etc.

The lower alkoxycarbonyl group includes a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.

The aminocarbonyl-substituted lower alkoxy group having optionally a lower alkyl group includes a straight chain or branched chain C₁ -C₆ alkoxy group, which has an aminocarbonyl group having optionally 1 to 2 straight chain or branched chain C₁ -C₆ alkyl group, for example, aminocarbonylmethoxy, 2-aminocarbonylethoxy, 1-aminocarbonylethoxy, 3-aminocarbonylpropoxy, 4-aminocarbonylbutoxy, 5-aminocarbonylpentyloxy, 6-aminocarbonylhexyloxy, 1,1-dimethyl-2-aminocarbonylethoxy, 2-methyl-3-aminocarbonylpropoxy, methylaminocarbonylmethoxy, 1-ethylaminocarbonylethoxy, 2-propylaminocarbonylethoxy, 1-ethylaminocarbonylethoxy, 2-propylaminocarbonylethoxy, 3-isopropylaminocarbonylpropoxy, 4-butylaminocarbonylbutoxy, 5-pentylaminocarbonylpentyloxy, 6-hexylaminocarbonylhexyloxy, dimethylaminocarbonylmethoxy, 2-diethylaminocarbonylethoxy, 2-dimethylaminocarbonylethoxy, (N-ethyl-N-propylamino)carbonylmethoxy, 2-(N-methyl-N-hexylamino)carbonylethoxy, etc.

The amino-substituted lower alkyl group having optionally a lower alkyl substituent includes a straight chain or branched chain C₁ -C₆ alkyl group which is substituted by an amino group having optionally 1 to 2 C₁ -C₆ alkyl substituents, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, (N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl, etc.

The 5- to 12-membered saturated heteromonocyclic, heterobicyclic or heterospirocyclic group which is formed by combining R¹² and R¹³ together with the adjacent nitrogen atom to which they bond with or without being intervened with another nitrogen atom or an oxygen atom includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, homopiperazinyl, homomorpholino, 1,4-diazabicyclo[4.3.0]nonyl, 1,4-diazabicyclo[4.4.0]decyl, 1,4-diazaspiro[5.5]undecyl, etc.

The lower alkoxy-substituted lower alkyl group includes a straight chain or branched chain C₁ -C₆ alkyl group which has 1 to 3 straight chain or branched chain C₁ -C₆ alkoxy groups, for example, methoxymethyl 3-methoxypropyl, ethoxymethyl, 2-methoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-isopropoxypentyl, 6-propoxyhexyl, 1,1-dimethyl-2-butoxyethyl, 2-methyl-3-tert-butoxypropyl, 2-pentyloxyethyl, hexyloxymethyl, etc.

The amino group having optionally a lower alkyl substituent includes an amino group having optionally 1 to 2 straight chain or branched chain C₁ -C₆ alkyl groups, for example, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, etc.

The above heterocyclic group having a substituent selected from a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower alkoxycarbonyl group, an amino group having optionally a lower alkyl substituent and a hydroxy-substituted lower alkyl group includes the above mentioned heterocyclic groups having 1 to 3 substituents selected from a straight chain or branched chain C₁ -C₆ alkyl group, a straight chain or branched chain C₁ -C₆ alkyl group which has 1 to 3 straight chain or branched chain C₁ -C₆ alkoxy group, a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, an amino group having optionally 1 to 2 straight chain or branched chain C₁ -C₆ alkyl groups and a straight chain or branched chain C₁ -C₆ alkyl group which has 1 to 3 hydroxy substituents, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 4-ethylpiperazinyl, 4-methylhomopiperazinyl, 4-dimethylaminopiperidinyl, 4-tert-butoxycarbonylhomopiperazinyl, 4-n-butylhomopiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 3-methylpiperazinyl, 4-(1,3-dihydroxy-2-propyl)piperazinyl, 4-(1,3-dihydroxy-2-propyl)homopiperazinyl, 3,4,5-trimethylpiperazinyl, 4-isopropylpiperazinyl, 3,3,4-trimethylpiperazinyl, 4,5-dimethylhomopiperazinyl, 3-methyl-4-ethylpiperazinyl, 3-methyl-4-n-propylpiperazinyl, 3-n-propyl-4-methylpiperazinyl, 3-methyl-4-isopropylpiperazinyl, 3-ethyl-4-methylpiperazinyl, 3-methyl-4-(2-methoxyethyl)piperazinyl, 3-methyl-4-(2-hydroxyethyl)piperazinyl, 3-isopropyl-4-methylpiperazinyl, 4-methyl-1,4-diazasprio[5.5]undecyl, 3-amino-1,4-diazabicyclo[4.4.0]decyl, 5-hydroxymethyl-1,4-diazabicyclo[4.3.0]nonyl, 3-ethoxycarbonylhomomorpholino, 3-diethylaminomorpholino, 3-methoxymethylpyrrolidinyl, etc.

The lower alkyl group having optionally a halogen substituent includes, for example, in addition to the above lower alkyl groups and halogen-substituted lower alkyl groups.

The pyridyl group having optionally a lower alkyl substituent which may optionally have a halogen substituent on the pyridine ring includes a pyridyl group having 1 to 3 straight chain or branched chain C₁ -C₆ alkyl groups which may optionally 1 to 3 halogen substituents on the pyridine ring, for example, pyridyl, 3-methylpyridyl, 4-ethylpyridyl, 2-propylpyridyl, 3-butylpyridyl, 4-pentylpyridyl, 4-hexylpyridyl, 3,4-dimethylpyridyl, 3,4,5-trimethylpyridyl, 3-trifluoromethylpyridyl, 2-chloromethylpyridyl, 4-(5-bromohexyl)pyridyl, 3-iodomethylpyridyl, 4-(2,2,2,-trifluoroethyl)pyridyl, 4-(5,6-dichlorohexyl)pyridyl, etc.

The cycloalkyl group includes a C₃ -C₈ cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

The tetrahydropyranyloxy-substituted lower alkyl group includes a tetrahydropyranyloxy-substituted alkyl group wherein the alkyl moiety is a straight chain or branched chain C₁ -C₆ alkyl group, for example, (2-tetrahydropyranyl)oxymethyl, 2-(3-tetrahydropyranyl)oxyethyl, 1-(4-tetrahydropyranyl)oxyethyl, 3-(2-tetrahydropyranyl)oxypropyl, 4-(3-tetrahydropyranyl)oxybutyl, 5-(4-tetrahydropyranyl)oxypentyl, 6-(2-tetrahydropyranyl)oxyhexyl, 1,1-dimethyl-2-(3-tetrahydropyranyl)oxyethyl, 2-methyl-3-(4-tetrahydropyranyl)oxypropyl, etc.

The phenyl-lower alkyl group includes a phenylalkyl group wherein the alkyl moiety is a straight chain or branched chain C₁ -C₆ alkyl group, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl, etc.

The phenyl-lower alkoxy group includes a phenylalkoxy group wherein the alkoxy moiety is a straight chain or branched chain C₁ -C₆ alkoxy group, for example, benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1,1-dimethyl-2-phenylethoxy, 2-methyl-3-phenylpropoxy, etc.

The lower alkanoyloxy group includes a straight chain or branched chain C₁ -C₆ alkanoyloxy group, for example, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, hexanoyloxy, etc.

The piperidinyl group having optionally a lower alkyl substituent on the piperidine ring includes a piperidinyl group having optionally a straight chain or branched chain C₁ -C₆ alkyl group, for example, piperidinyl, 1-methyl-4-piperidinyl, 1-ethyl-3-piperidinyl, 1-ethyl-2-piperidinyl, 1-propyl-4-piperidinyl, 1-butyl-4-piperidinyl, 1-pentyl-4-piperidinyl, 1-hexyl-4-piperidinyl, 1-isobutyl-3-piperidinyl, 1-tert-butyl-2-piperidinyl, etc.

The phenyl-lower alkyl group having optionally a lower alkylenedioxy substituent on the phenyl ring includes a phenylalkyl group having optionally a straight chain or branched chain C₁ -C₄ alkylenedioxy group on the phenyl ring wherein the alkyl moiety is a straight chain or branched chain C₁ -C₆ alkyl. group, in addition to the above phenyl-lower alkyl groups, for example, 3,4-methylenedioxybenzyl, 2-(3,4-ethylenedioxyphenyl)ethyl, 1-(3,4-ethylenedioxyphenyl)ethyl, 3-(2,3-trimethylenedioxyphenyl)propyl, 4-(3,4-tetramethylenedioxyphenyl)butyl, 5-(3,4-methylenedioxyphenyl)pentyl, 6-(2,3-trimethylenedioxyphenyl)hexyl, etc.

The lower alkylenedioxy group includes a straight chain or branched chain C₁ -C₄ alkylenedioxy group, for example, methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy, etc.

The 5- to 10-membered, saturated or unsaturated heteromonocyclic or heterobicyclic residue having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, 1-azabicyclooctyl, homopiperazinyl, homomorpholino, 1,4-diazabicyclo[4.3.0]nonyl, 1,4-diazabicyclo[4.4.0]decyl, pyridyl, 1,2,5,6-tetrahydropyridyl, thienyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, 1,3,4-triazoly, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazinyl, pyrrolyl, pyrrolinyl, carbostyril, 1,3-dioxolanyl, thiomorpholino, 3,4-dihydrocarbostyril, 1,2,3,4-tetrahydroquinolyl, 2,3,4,5-tetrahydrofuryl, indolyl, isoindolyl, 3H-indolyl, indolinyl, indolidinyl, indazolyl, benzimidazolyl, benzoxazolyl, imidazolinyl, imidazolidinyl, isoquinolyl, naphthylidinyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, thienyl, imidazolyl, pyrazolidinyl, benzofuryl, 2,3-dihydrobenzo[b]furyl, benzothienyl, tetrahydropyranyl, 4H-chromenyl, 1H-indazolyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, pyranyl, pyrazolidinyl, 2-pyrazolinyl, quinuclidinyl, 1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, 1,4-dithianaphthalenyl, 2,5-dihydrofurano[3.4-c]pyridyl, 2,3,4,5,6,7-hexahydro-1H-azepinyl, 1,2,3,4,5,6,7,8-octahydroazocinyl, 1,2,3,4,5,6, -tetrahydrooxepinyl, 1,3-dioxolanyl, 3,4,5,6-tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, etc.

The above heterocyclic groups having 1 to 3 substituents selected from (i) a lower alkyl group; (ii) a group: --(B)_(l) --NR¹² R¹³ (l is the same as defined above, B is a group: --CO--A-- (A is the same as defined above), a carbonyl group or a lower alkylene group, R¹² and R¹³ are the same or different, and each are a hydrogen atom, a lower alkyl group, an amino-substituted lower alkyl group having optionally a lower alkyl substituent, or combine together with the adjacent nitrogen atom to which they bond to form a 5- to 12-membered saturated heteromonocyclic, heterobicyclic or spiro-cyclic hetero ring with or without being intervened with another nitrogen atom or an oxygen atom, said heterocyclic group may optionally have a substituent selected from a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy-substituted lower alkyl group, an amino group having optionally a lower alkyl substituent and a hydroxy-substituted lower alkyl group); (iii) a lower alkoxycarbonyl group; (iv) a hydroxy-substituted lower alkyl group; (v) a pyridyl group being optionally substituted by a lower alkyl group having optionally a halogen substituent on the pyridine ring; (vi) a halogen-substituted lower alkyl group; (vii) a lower alkoxy group; (viii) a cycloalkyl group; (ix) a hydroxy group; (x) a tetrahydropyranyloxy-substituted lower alkyl group; (xi) a pyrimidyl group; (xii) a lower alkoxy-substituted lower alkyl group; (xiii) a carboxyl group; (xiv) a phenyl-lower alkoxy group; (xv) a phenyl-lower alkyl group having optionally a lower alkylenedioxy substituent on the phenyl ring; (xvi) a lower alkanoyloxy group; and (xvii) a piperidinyl group having optionally a lower alkyl substituent on the piperidine ring includes the above heterocyclic groups having 1 to 3 substituents selected from (i) a straight chain or branched chain C₁ -C₆ alkyl group; (ii) a group: --(B)_(l) --NR¹² R¹³ (l is the same as defined above, B is a group: --CO--A-- (A is the same as defined above), a carbonyl group or a straight chain or branched chain C₁ -C₆ alkylene group, R¹² and R¹³ are the same or different, and each are a hydrogen atom, a straight chain or branched chain C₁ -C₆ alkyl group, or a straight chain or branched chain C₁ -C₆ alkyl group which has an amino group having optionally 1 to 2 straight chain or branched chain alkyl substituents, or both combine together with the adjacent nitrogen atom to which they bond to form a 5- to 12-membered saturated heteromonocyclic, heterobicyclic or sprio-cyclic hetero ring with or without being intervened with another nitrogen atom or an oxygen atom, said heterocyclic group may optionally have 1 to 3 substituents selected from a straight chain or branched chain C₁ -C₆ alkyl group, a straight chain or branched chain C₁ -C₆ alkyl group which has 1 to 3 straight chain or branched chain C₁ -C₆ alkoxy substituents, a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, an amino group having optionally 1 to 2 straight chain or branched chain C₁ -C₆ alkyl substituent and a straight chain or branched chain C₁ -C₆ alkyl group having 1 to 3 hydroxy substituents); (iii) an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety; (iv) a straight chain or branched chain C₁ -C₆ alkyl group having 1 to 3 hydroxy substituents; (v) a pyridyl group having optionally 1 to 3 straight chain or branched chain C₁ -C₆ alkyl groups which have optionally 1 to 3 halogen substituents on the pyridine ring; (vi) a straight chain or branched chain C₁ -C₆ alkyl group having 1 to 3 halogen substituents; (vii) a straight chain or branched chain C₁ -C₆ alkoxy group; (viii) a C₃ -C₈ cycloalkyl group; (ix) a hydroxy group; (x) a tetrahydropyranyloxy-substituted alkyl group wherein the alkyl moiety is a straight chain or branched chain C₁ -C₆ alkyl group; (xi) a pyrimidyl group; (xii) a straight chain or branched chain C₁ -C₆ alkyl group having 1 to 3 straight chain or branched chain C₁ -C₆ alkoxy substituents; (xiii) a carboxyl group; (xiv) a phenyl alkoxy group wherein the alkoxy moiety is a straight chain or branched chain C₁ -C₆ alkoxy group; (xv) a phenylalkyl group having optionally a straight chain or branched chain C₁ -C₄ alkylenedioxy substituent on the phenyl ring, wherein the alkyl moiety is a straight chain or branched chain C₁ -C₆ alkyl group; (xvi) a straight chain or branched chain C₁ -C₆ alkanoyloxy group; and (xvii) a piperidinyl group having optionally 1 to 3 straight chain or branched chain C₁ -C₆ alkyl substituents on the piperidine ring, for example, 4-methylpiperazinyl, 4-(4-methyl-1-piperazinyl)piperidinyl, 2-(4-methyl-1-piperazinylmethyl)morpholino, 2-(4-methyl-1-piperazinylmethyl)pyrrolidinyl, 3-(4-methyl-1-piperazinyl)pyrrolidinyl, 1-ethyl-1,2,3,4-tetrazolyl, 1-tert-butoxycarbonylpiperidinyl, 1-methylpiperidinyl, 2,2-dimethyl-1,3-dioxolanyl, 4-(3,4-dimethyl-1-piperazinyl)piperidinyl, 4-(4-ethyl-1-piperazinyl)piperidinyl, 4-[N-(2-diethylaminoethyl)-N-methylamino]piperidinyl, 4-(4-methyl-1-homopiperazinyl)piperidinyl, 2-(4-ethyl-1-piperazinylmethyl)morpholino, 4-dimethylaminopiperidinyl, 2-morpholinomethylpyrrolidinyl, 4-(1-pyrrolidinyl)piperdinyl, 4-isopentylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(1-pyrrolidinylmethyl)morpholino, 4-morpholinopiperidinyl, 2-aminomethylmorphlino, 1-dimethylaminomethylcarbonylpiperidinyl, 1-methylimidazolyl, 4-(2-pyridyl)piperazinyl, 4-(3,4-methylenedioxybenzyl)piperazinyl, 1-(4-chlorobutyl)-1,2,3,4-tetrazolyl, 2-methoxycarbonylpyridyl, 2-carboxypyridyl, 4-isopropylpyridyl, 4-hydroxypiperidinyl, 2-methyl-3-hydroxy-2,5-dihydrofuran[3,4-c]pyridyl, 1-cyclohexyl-1,2,34-tetrazolyl, 3-(4-methyl-1-piperazinyl)pyrrolidinyl, 1-[(3-3,4,5,6-tetrahydro-2H-pyranyl)methyl]-1,2,3,4-tetrazolyl, 1-(3-chloropropyl)-1,2,3,4-tetrazolyl, 2-carbamoylpyrrolidinyl, 4-(3-trifluoromethyl-2-pyridyl)piperazinyl, 4-benzylpiperidinyl, 4-n-butyl-1,2,3,4-tetrazolyl, 4-carbamoylpiperidinyl, 2-(4-methyl-1-piperazinyl)homomorpholino, 2-methylmorpholino, 2-methoxymethylmorpholino, 2-chloromethylmorpholino, 2-hydroxymethylmorpholino, 2-n-butoxymethylmorpholino, 2-(4-methyl-1-homopiperazinylmethyl)morpholino, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolyl, 2-(4-methyl-1-homopiperazinylmethyl)homomorpholino, 2-chloromethylhomomorpholino, 2-hydroxymethylhomomorpholino, 4-hydroxypiperazinyl, 2-methoxymethyl-1,2,3,4,5,6-hexahydrooxepinyl, 4-(2-phenylethoxy)piperidinyl, 4-benzyloxypiperidinyl, 4-hydroxy-3-methylpiperazinyl, 4-methylhomopiperazinyl, 4-acetyloxypiperazinyl, 4-methoxypiperazinyl, 4-(4-tert-butoxycarbonyl-1-homopiperazinyl)piperidnyl, 4-(4-n-butyl-1-homopiperazinyl)piperidinyl, 4-(1-methyl-4-piperidinyl)homopiperazinyl, 3-(4-methyl-1-homopiperazinyl)piperidinyl, 2-(4-dimethylamino-1-piperidinylmethyl)morpholino, 2-(4-methyl-1-piperazinylmethyl)homomorpholino, 2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]morpholino, 4-(3-methyl-1-piperazinyl)piperidinyl, 4-(4-ethyl-1-homopiperazinyl)piperidinyl, 3-(4-methyl-1-homopiperazinyl)pyrrolidinyl, 4-[4-(1,3-dihydroxy-2-propyl)-1-piperazinyl]piperidinyl, 4-[4-(1,3-dihydoxy-2-propyl)-1-homopiperazinyl]piperidnyl, 4-methyl-3-(1-piperidinylmethyl)piperazinyl, 4-methyl-3-(4-methyl-1-piperazinylmethyl)piperazinyl, 4-methyl-3-(4-methyl-1-homopiperazinylmethyl)piperazinyl, 3,4,5-trimethoxypiperazinyl, 4-isopropylpiperazinyl, 4-(1,4-diazabicyclo[4.3.0]nonyl)piperidinyl, (3,3,4-trimethyl-1-piperazinyl)piperidinyl, 4-(1,4-diazabicyclo[4.4.0]decyl)piperidinyl, 4-(3-methyl-4-ethyl-1-piperazinyl)piperidinyl, 4-(3-methyl-4-propyl-1-piperazinyl)piperidinyl, 4-(3-propyl-4-methyl-1-piperazinyl)piperidinyl, 4-(3-methyl-4-isopropyl-1-piperazinyl)piperidinyl, 4-(3-ethyl-4-methyl-1-piperazinyl)piperidinyl, 4-[3-methyl-4-(2-methoxyethyl)-1-piperazinyl]piperidinyl, 4-[3-methyl-4-(2-hydroxyethyl)-1-piperazinyl]piperidinyl, 4-(4-methyl-1-1,4-diazaspiro[5.5]undecyl)piperidinyl, 4-(4-methyl-3-isopropyl-1-piperazinyl)piperidinyl, 4-(2-pyrimidyl)piperazinyl, etc.

The lower alkenyloxy group includes a C₂ -C₆ straight chain or branched chain alkenyloxy group, for example, vinyloxy, 1-methylvinyloxy, 2,2-dimethylvinyloxy, 1,2-dimethylvinyloxy, 1-propylvinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 1-ethylvinyloxy, 1-methylallyloxyl, 1-pentenyloxy, 2-pentenyloxy, 2-hexenyloxy, 3-methyl-1-butenyloxy, 1-butenyloxy, etc.

The cycloalkyloxy group includes a C₃ -C₈ cycloalkyloxy group, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, etc.

The lower alkylthio group includes a C₁ -C₆ straight chain or branched chain alkylthio group, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, etc.

The lower alkenyl group includes a C₂ -C₆ straight chain or branched chain alkenyl group, for example, vinyl, 1-methylvintyl, 2,2-dimethylvinyl, 1,2-dimethylvinyl, 1-propenylvinyl, allyl, 2-butenyl, 3-butenyl, 1-ethylvinyl, 1-methylallyl, 1-pentenyl, 2-pentenyl, 2-hexenyl, 3-methyl-1-butenyl, 1-butenyl, etc.

The present invention specifically includes the following compounds.

(1) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR9## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(2) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR10## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group, and u is 0, or a salt thereof.

(3) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR11## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(4) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR12## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group, and u is 1, or a salt thereof.

(5) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR13## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(6) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR14## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(7) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR15## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(8) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR16## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(9) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR17## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(10) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR18## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(11) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR19## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(12) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR20## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(13) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR21## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(14) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR22## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(15) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR23## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(16) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR24## (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(17) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR25## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(18) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR26## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(19) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR27## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(20) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR28## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(21) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR29## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(22) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR30## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(23) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR31## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(24) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR32## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(25) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR33## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(26) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR34## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(27) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR35## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(28) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR36## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(29) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR37## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(30) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR38## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(31) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR39## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(32) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR40## (s is 0, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m, A and Z are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(33) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different, and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR41## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(34) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different, and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR42## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(35) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different, and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR43## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(36) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different, and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR44## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(37) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR45## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(38) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR46## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(39) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR47## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(40) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR48## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(41) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR49## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(42) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR50## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(43) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR51## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(44) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR52## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(45) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR53## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(46) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR54## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(47) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR55## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(48) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR56## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(49) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR57## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(50) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR58## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(51) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR59## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(52) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR60## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(53) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR61## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(54) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR62## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(55) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR63## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(56) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR64## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(57) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR65## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(58) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR66## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(59) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR67## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(60) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR68## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(61) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR69## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(62) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR70## (s is 1, Z is a sulfur atom, R⁶ is a group: --O--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(63) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR71## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(64) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR72## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) (R^(11b), p and R^(11a) are the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(65) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR73## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(66) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR74## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(67) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR75## s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as n the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(68) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR76## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(69) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the fornula: ##STR77## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(70) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR78## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(71) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the fornula: ##STR79## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(72) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR80## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(73) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR81## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(74) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR82## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(75) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR83## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(76) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR84## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(77) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR85## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(78) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR86## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(79) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR87## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(80) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR88## (s is 0, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, Z, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(81) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR89## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(82) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR90## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(83) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR91## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(84) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR92## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(85) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR93## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(86) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR94## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(87) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR95## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(88) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR96## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(89) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR97## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(90) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR98## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(91) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR99## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(92) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR100## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(93) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR101## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(94) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR102## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(95) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR103## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(96) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR104## (s is 1, Z is an oxygen atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(97) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR105## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(98) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR106## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(99) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR107## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(100) A thiazole derivative of the formula (1) wherein R¹ and R² are the same or different and each are a hydrogen atom or a lower alkyl group, R³ is a group of the formula: ##STR108## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(101) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR109## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(102) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR110## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(103) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR111## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(104) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4), R³ is a group of the formula: ##STR112## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(105) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR113## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(106) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR114## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(107) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR115## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(108) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5), R³ is a group of the formula: ##STR116## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

(109) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR117## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 0, or a salt thereof.

(110) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR118## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 0, or a salt thereof.

(111) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR119## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a hydrogen atom, and u is 1, or a salt thereof.

(112) A thiazole derivative of the formula (1) wherein R¹ and R² combine to form a benzene ring which may optionally have a substituent selected from a lower alkyl group, a lower alkoxy group, a nitro group, an amino group having optionally a lower alkyl substituent and a halogen atom, R³ is a group of the formula: ##STR120## (s is 1, Z is a sulfur atom, R⁶ is a group: --CO--C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined in the formula (1)), R⁵, m and A are the same as defined in the formula (1)), R⁴ is a lower alkanoyloxy-lower alkyl group and u is 1, or a salt thereof.

The compounds of the present invention of the formula (1) may be prepared by various processes, but preferably prepared by the following processes. ##STR121## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined above, R¹⁵ is a group: --CH═C(R^(11b))(COR¹⁶) (R^(11b) is the same as defined above, and R¹⁶ is a hydroxy group or a lower alkoxy group), or a group: --C.tbd.C--COR¹⁴ (R¹⁴ is the same as defined above), and X is a halogen atom.

The reaction between the compound (2) and the compound (3) or the compound (4) is called Friedel-Crafts Reaction, and carried out in the presence of a Lewis acid in a suitable solvent. The Lewis acid may be any conventional Lewis acids which are used in this kind of Friedel-Crafts Reaction, and is, for example, aluminum chloride, zinc chloride, iron chloride, stannous chloride, boron tribromide, boron trifluoride, conc. sulfuric acid, etc. The solvent may be, for example, carbon disulfide, aromatic hydrocarbons such as nitrobenzene, chlorobenzene, halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon tetrachloride, tetrachloroethane, aliphatic nitro compounds such as nitroethane, nitromethane, or a mixture of these solvents. The compound (3) and the compound (4) are used each at least in an equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (2). The Lewis acid is usually used in an a mount of 1 to 6 moles, to 1 mole of the compound (2). The reaction is usually carried out at 0 to 120° C., preferably at 0 to 70° C., for about 0.5 to 24 hours.

The compound wherein R¹⁵ is a group: --CH═C(R^(11b))(COR¹⁶), and the double bond thereof shows a cis-configuration can be isomerized into the compound wherein the double bond shows a trans-configuration by heating it at about 50° C. to 100° C. in dimethylformamide.

The compound (1a) wherein R¹⁵ is a group: --CH═C(R^(11b))(COR¹⁶) or a group: --C.tbd.C--COR¹⁴, and R¹⁶ and R¹⁴ are both a lower alkoxy group may be converted into a compound (1a) wherein a corresponding R¹⁶ and R¹⁴ are a hydroxy group, by treating it under the same conditions as in the reaction of converting the compound (1d) into the compound (1e) in Reaction Scheme 4, described hereinbelow. ##STR122## wherein R¹, R², R⁴, R⁵, R^(11b), Z, m, s, T, u and A are the same as defined above, R¹⁷ is the heterocyclic residues as defined for R^(11a) but having at least one ##STR123## in the heterocyclic nucleus.

The process of Reaction Scheme-2 is a conventional amido bond producing reaction, and is carried out by reacting the thiazole compound (1b) and the amine compound (5). The amido bond producing reaction can be carried out under the same conditions as those of the conventional amino bond producing reaction, for example,

(a) a mixed acid anhydride process, i.e. a process of reacting the carboxylic acid compound (1b) with an alkyl halocarbonate to form a mixed acid anhydride and reacting the resultant with the amine compound (5);

(b) an activated ester process, i.e. a process of converting the carboxylic acid compound (1b) into an activated ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and reacting the resultant with the amine compound (5);

(c) a carbodiimide process, i.e. a process of condensing the carboxylic acid compound (1b) and the amine compound (5) in the presence of an activating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc.;

(d) other processes, i.e. a process of converting the carboxylic acid compound (1b) into a carboxylic anhydride by treating it with a dehydrating agent such as acetic anhydride, and reacting the resultant with the amine compound (5); a process of reacting an ester of the carboxylic acid compound (1b) with a lower alcohol and the amine compound (5) at high temperature under high pressure; a process of reacting an acid halide compound of the carboxylic acid compound (1b), i.e. a carboxylic acid halide, with the amine compound (5).

The mixed acid anhydride used in the above mixed acid anhydride process (a) is obtained by the known Schotten-Baumann reaction, and the reaction product is used without isolating from the reaction mixture for the reaction with the amine compound (5) to give the desired compound (1) of the present invention. The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. The basic compound is any conventional compounds used for the Schotten-Baumann reaction and includes, for example, organic basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc., and inorganic basic compounds such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. The reaction is usually carried out at a temperature from about -20° C. to about 100° C., preferably at a temperature of -20° C. to about 50° C., for about 5 minutes to about 10 hours, preferably for 5 minutes to about 2 hours.

The reaction between the mixed acid anhydride thus obtained and the amine compound (5) is usually carried out at a temperature of -20° C. to about 150° C., preferably at a temperature of -20° C. to about 50° C., for about 5 minutes to about 35 hours, preferably for about 5 minutes to 30 hours. The mixed acid anhydride process is usually carried out in a solvent in the presence of a basic compound. The basic compounds may be any basic compounds used in the above Schotten-Baumann reaction. The solvent may be any conventional solvents which are usually used in the mixed acid anhydride process and includes, for example, halogenated hydrocarbons (e.g. chloroform, dichloromethane, dichloroethane, etc.), aromatic hydrocarbons (e.g. benzene, p-chlorobenzene, toluene, xylene, etc.), ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoric triamide, 1-methyl-2-pyrrolidinone (NMP), etc.), or a mixture of these solvents. The alkyl halocarbonate used in the mixed acid anhydride process includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. In said process, the carboxylic acid compound (1b), the alkyl halocarbonate ester and the amine compound (5) are usually used in equimolar amount each, but preferably the alkyl halocarbonate ester and the amine compound (5) are used in an amount of about 1 to 1.5 mole, to 1 mole of the carboxylic acid (1b).

Among the above other processes (d), in case of the process of reacting the carboxylic acid halide with the amine compound (5), the reaction is usually carried out in the presence of a basic compound in a suitable solvent. The basic compound is any conventional basic compounds and includes, for example, in addition to the basic compounds used in the above mentioned Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, and the like. The solvent includes, for example, in addition to the solvents used in the mixed acid anhydride process, alcohols (e.g. methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve, methylcellosolve, etc.), pyridine, acetone, water, or a mixture of two or more these solvents, and the like. The amount of the amine compound (5) and the carboxylic acid halide is not critical, but the amine compound (5) is usually used at least in equimolar amount, preferably in an amount of about 1 to 5 moles, to 1 mole of the carboxylic acid halide. The reaction is usually carried out at a temperature of about -70° C. to about 180° C., preferably at a temperature of about -50° C. to about 150° C., for about 5 minutes to about 30 hours.

Besides, the amido bond producing reaction of Reaction Scheme-2 may also be carried out by reacting the carboxylic acid compound (1b) and the amine compound (5) in the presence of a condensing agent such as phosphorus compounds (e.g. phenylphosphine-2,2'-dithiopyridine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl cyanophosphate, diethyl cyanophosphate, diphenylphosphoryl azide, N,N'-bis(2-oxo-3-oxazolidinyl)phosphinic chloride, etc.).

The reaction is usually carried out in the presence of the same solvent and the same basic compound which can be used in the above reaction of the carboxylic acid halide compound and the amine compound (5). The reaction is usually carried out at a temperature of -20° C. to about 150° C., preferably at a temperature of 0° C. to about 100° C., for about 5 minutes to about 30 hours. The condensing agent and the amine compound (5) are used at least in equimolar amount, preferably in an amount of about 1 to 2 moles, to 1 mole of the carboxylic acid compound (1b). ##STR124## wherein R¹, R², R³, R⁴, R⁵, Z, m, s, T, u, R¹⁶ and A are the same as defined above, R¹⁸ and R¹⁹ are a lower alkoxy group, and R²² is the same as defined below.

The reaction of the compound (6) and the compound (7) is carried out in the presence of a basic compound in a suitable solvent. The basic compound includes inorganic basic compounds such as metal sodium, metal potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc., organic basic compounds such as alkali metal alkoxide (e.g., sodium methylate, sodium ethylate, potassium t-butoxide), an alkyl lithium, aryl lithium or lithium amide (e.g., methyl lithium, n-butyl lithium, phenyl lithium, lithium diisopropylamide), pyridine, piperidine, quinoline, triethylamine, N,N-dimethylaniline, etc. The solvent may be any one which does not disturb the reaction, for example, water, ethers (e.g., diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g., n-hexane, heptane, cyclohexane, etc.), amines (e.g., pyridine, N,N-dimethylaniline, etc), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), ureas (e.g., N,N'-dimethylpropylene urea (DMPU), etc.), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, or a mixture of these solvents. The reaction is usually carried out at -80° C. to 150° C., preferably at about -80° to 120° C., for 0.5 to about 15 hours.

The compound (7) is usually used at least in an equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (6).

The reaction of converting the compound (8) into the compound (10) is carried out in the presence of an oxidizing agent in a suitable solvent. The oxidizing agent includes, for example, benzoquinones (e.g., 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)), pyridinium chromates (e.g., pyridinium chlorochromate, pyridium dichlorochromate, etc.), dimethylsulfoxide-oxazolyl chloride, dichromic acid, dichromates (e.g. sodium dichromate, potassium dichromate, etc.), permanganic acid, permanganates (e.g. potassium permanganate, sodium permanganate, etc.), manganese dioxide, etc. The solvent includes, for example, water, organic acids (e.g. formic acid, acetic acid, trifluoroacetic acid, etc.), alcohols (e.g. methanol, ethanol, .etc.), halogenated hydrocarbons (e.g. chloroform, dichloromethane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, etc.), dimethylsulfoxide, dimethylformamide, or a mixture of these solvents. The oxidizing agent is preferably used in an excess amount to the amount of the starting compound. The above reaction is usually carried out at 0° C. to 200° C., preferably at 0° C. to about 150° C., for 1 hour to about 10 hours.

The reaction of the compound (9) and the compound (7) is carried out under the same conditions as those in the reaction of the compound (6) and the compound (7).

The reaction of the compound (10) and the compound (12) is carried out under the same conditions as those in the reaction of the compound (6) and the compound (7).

The reaction of the compound (10) and the compound (20) is carried out under the same conditions as those in the reaction of the compound (6) and the compound (7). ##STR125## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined above, R²⁰ is a lower alkoxy group, M is an alkali metal such as lithium, sodium, potassium, etc., and R^(16a) is a lower alkoxy group.

The reaction of the compound (6) and the compound (13) is carried out in the presence of a basic compound in a suitable solvent, at -80° C. to room temperature, for 5 minutes to 6 hours. The solvent may be, for example, ethers (e.g., diethyl ether, dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g., benzene, toluene, etc.), saturated hydrocarbons (e.g., hexane, heptane, pentane, cyclohexane, etc.), ureas (e.g., N,N'-dimethylpropyleneurea (DMPU), etc.). The basic compounds are the same ones which are used in the reaction of the compound (6) and the compound (7) in the above Reaction Scheme-3. The compound (13) is usually used at least in equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (6).

The reaction of converting the compound (11) into the compound (1d') is carried out in the presence of a basic compound in a suitable solvent. The basic compound may be organic basic compound such as triethylamine, trimethylamine, diisopropylamine, tri-n-butylamine, ethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, DABCO, etc. The solvent includes, for example, water, alcohols (e.g., ethanol, methanol, isopropanol, etc.), dimethylformamide, diemthylsulfoxide, hexamethylphosphoric triamide, or a mixture of these solvents. The reaction is usually carried out at room temperature to 150° C., preferably at room temperature to 100° C., for about 1 to 5 hours.

The reaction of converting the compound (11) into the compound (1f) is carried out under the same conditions as those in the reaction of converting the compound (8) into the compound (10) in the above Reaction Scheme-3.

The reaction of converting the compound (1d') into the compound (1e) is carried out in the presence of an acid or a basic compound in a suitable solvent, or without a solvent. The solvent includes, for example, water, lower alcohols (e.g., ethanol, methanol, isopropanol, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), ethers (e.g., dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g., acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g., hydrochloric acid, sulfuric acid; hydrobromic acid, etc.), organic acids (e.g., formic acid, acetic acid, trifluoric acid, aromatic sulfuric acids, etc.). The basic compound includes, for example, an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, etc.), etc. The reaction is usually carried out at room temperature to about 200° C., preferably at room temperature to 150° C., for about 10 minutes to 25 hours.

The reaction of converting the compound (1f) into the compound (1g) is carried out under the same conditions as those in the reaction of converting the compound (1d') into the compound (1e) as mentioned above. ##STR126## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined above, X¹ is a halogen atom, R²¹ is a phenyl group, R²² is a 5- to 10-membered, saturated or unsaturated heteromonocyclic, heterobicyclic residue (said heterocyclic residue optionally having 1 to 3 substituents selected from (i) a lower alkyl group; (ii) a group: --(B)_(l) --NR¹² R¹³ (l is the same as defined above, B is a group: --CO--A-- (A is the same as defined above), a carbonyl group or a lower alkylene group, R¹² and R¹³ are the same or different, and each are a hydrogen atom, a lower alkyl group, an amino-substituted lower alkyl group having optionally a lower alkyl substituent, or combine together with the adjacent nitrogen atom to which they bond to form a 5- to 12-membered saturated heteromonocyclic, heterobicyclic or hetero-sprio ring with or without being intervened with another nitrogen atom or an oxygen atom, said heterocyclic group may optionally have a substituent selected from a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy-substituted lower alkyl group, an amino group having optionally a lower alkyl substituent and a hydroxy-substituted lower alkyl group); (iii) a lower alkoxycarbonyl group; (iv) a hydroxy-substituted lower alkyl group; (v) a pyridyl group being optionally substituted by a lower alkyl group having optionally a halogen substituent on the pyridine ring; (vi) a halogen-substituted lower alkyl group; (vii) a lower alkoxy group; (viii) a cycloalkyl group; (ix) a hydroxy group; (x) a tetrahydropyranyloxy-substituted lower alkyl group; (xi) a pyrimidyl group; (xii) a lower alkoxy-substituted lower alkyl group; (xiii) a carboxyl group; (xiv) a phenyl-lower alkoxy group; (xv) a phenyl-lower alkyl group having optionally a lower alkylenedioxy substituent on the phenyl ring; (xvi) a lower alkanoyloxy group; and (xvii) a piperidinyl group having optionally a lower alkyl substituent on the piperidine ring.

The reaction of the compound (2) and the compound (14), and the reaction of the compound (2) and the compound (15) are carried out under the same conditions as those in the reaction of the compound (2) and the compound (3) or the compound (4) in the above Reaction Scheme-1.

The halogenating reaction of the compound (16) is carried out in the presence of a halogenating agent in a suitable solvent. The halogenating agent may be, for example, halogen molecules (e.g., bromine, chlorine, etc.), iodine chloride, sulfuryl chloride, copper compounds (e.g., copper (II) bromide, etc.), N-halogenated succinimides (e.g., N-bromosuccinimide, N-chlorosuccinimide, etc.). The solvent may be, for example, halogenated hydrocarbons (e.g., dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), fatty acids (e.g., acetic acid, propionic acid, etc.), carbon disulfide, etc. The halogenating agent is usually used in an amount of 1 to 10 moles, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (16). The reaction is usually carried out at 0° C. to a boiling point of the solvent to be used, preferably at 0° C. to 100° C., for about 5 minutes to 20 hours.

The reaction of the compound (17) and the compound (18) is carried out in a suitable solvent at room temperature to 150° C., preferably at room temperature to about 100° C., for about 1 hour to 10 hours. The solvent may be the same solvents used in the reaction of the carboxylic halide and the amine compound (5) among the reactions between the compound (1b) and the compound (5) in the above Reaction Scheme-2. The compound (18) is used at least in equimolar amount, preferably in an amount of 1 to 1.5 moles, to 1 mole of the compound (17).

In the above process, there is obtained a compound of the formula (21): ##STR127## wherein R¹, R², R⁴, R⁵, Z, m, A, R²¹, s, T, u and X are the same as defined above, which is further treated in the presence of a basic compound in a suitable solvent to give the compound (19). The solvent and the basic compound are the same ones which are used in the reaction of the carboxylic halide and the amine compound (5) in the reaction of the compound (1b) and the compound (5) in the Reaction Scheme-2. The reaction is usually carried out at 0° C. to 100° C., preferably at 0° C. to about 70° C., for about 1 hour to 5 hours.

The reaction of the compound (19) and the compound (20) is carried out under the same conditions as those in the reaction of the compound (6) and the compound (7) in the above Reaction Scheme-3.

Alternatively, the reaction of the compound (19) and the compound (20) is usually carried out in a suitable solvent at 0° C. to 150° C., preferably at room temperature to about 100° C., for about 0.5 hour to 8 hours. The solvent may be any one which does not disturb the reaction, for example, water, alcohols (e.g., methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, diglyme, monoglyme, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), etc. The compound (20) is usually used at least in equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (19). The reaction is promoted when a para-aldehyde is added into the reaction system. ##STR128## wherein R¹, R², R⁴, R⁵, R⁶, Z, s, T, u and A are the same as defined above, q is 1, R^(5a) is a halogen-substituted lower alkyl group, R^(5b) is a group: --A--NR⁷ R⁸ (A, R⁷, R⁸ are the same as defined above) or a lower alkanoyloxy-lower alkyl group, R²³ is a group: --NR⁷ R⁸ (R⁷ and R⁸ are the same as defined above), or a lower alkanoyloxy group.

The reaction of the compound (1f) and the compound (22) is carried out in the presence or absence of a basic compound in a suitable inert solvent, or without a solvent. The inert solvent includes, for example, aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), ethers (e.g., tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), lower alcohols (e.g., methanol, ethanol, isopropanol, butanol, tert-butanol, etc.), water, acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, or a mixture of these solvents. The basic compound includes, for example, an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an alkali metal hydrogen carbonate (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), sodium hydride, potassium, sodium, sodium amide, an alkali metal alkoxide (e.g., sodium methoxide, etc.), organic basic compounds (e.g., pyridine, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo[4.3.0]nonen-5-(DBN), 1,8-diazabicyclo[5.4.0]undecen-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc. The amount of the compound (1i) and the compound (22) is not critical, but the compound (22) is usually used at least in equimolar amount, preferably in an amount of 1 to 10 moles, to 1 mole of the compound (1i). The reaction is usually carried out at 0° C. to 200° C., preferably at 0° C. to 170° C., for about 30 minutes to 75 hours. Into the reaction system, an alkali metal halide such as sodium iodide, potassium iodide or a copper powder may be added. ##STR129## wherein R¹, R², R³, R⁴, T and u are the same as defined above.

The reaction of the compound (23) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (1b) and the compound (5) in the above Reaction Scheme-2. ##STR130## wherein R¹, R², R³, T, X and u are the same as defined above, and R^(4a) is a lower alkanoyloxy-lower alkyl group.

The reaction of the compound (1k) and the compound (25) is carried out under the same conditions as those in the reaction of the compound (1i) and the compound (22) in the above Reaction Scheme-6. ##STR131## wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, Z, s, T, u and q are the same as defined above, and R^(5c) is a carboxy-substituted lower alkyl group, R^(5d) is a group: --A--CO--NR⁷ R⁸ (R⁷ and R⁸ are the same as defined above).

The reaction of the compound (1m) and the compound (26) is carried out under the same conditions as those in the reaction of the compound (1b) and the compound (5) in the above Reaction Scheme-2.

The starting compounds (2), (6) and (23) in the above Reaction Schemes are prepared by the following processes. ##STR132## wherein R¹, R², R⁴, R⁵, X, Z, T, u and m are the same as defined above, and R²⁴ is a hydroxy group, a lower alkoxy group or a phenyl-lower alkoxy group, and A' is a lower alkylene group.

The reaction of the compound (27) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (1i) and the compound (22) in the above Reaction Scheme-6.

The reaction of converting the compound (29) wherein R²⁴ is a lower alkoxy group into the compound (30) is carried out under the same conditions as those in the reaction of converting the compound (1d) into the compound (1e) in the above Reaction Scheme-4.

The reaction of converting the compound (29) wherein R²⁴ is a phenyl-lower alkoxy group into the compound (30) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in Reaction Scheme-13, which is described hereinbelow.

The reaction of the compound (30) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (1b) and the compound (5) in the above Reaction Scheme-2. ##STR133## wherein R¹, R², R⁴, R⁵, A', Z, R²⁴, T, u and m are the same as defined above.

The reaction of the compound (31) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (27) and the compound (28) in the above Reaction Scheme-10.

The reaction of converting the compound (32) wherein R²⁴ is a lower alkoxy group into the compound (33) is carried out under the same conditions as those in the reaction of converting the compound (29) wherein R²⁴ is a lower alkoxy group into the compound (30) in the above Reaction Scheme-10.

The reaction of converting the compound (32) wherein R²⁴ is a phenyl-lower alkoxy group into the compound (33) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in Reaction Scheme-13, which is described hereinbelow.

The reaction of the compound (33) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (30) and the compound (24) in the above Reaction Scheme-10. ##STR134## wherein R⁵, R⁶, m, A', X, Z and R²⁴ are the same as defined above.

The reaction of the compound (34) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (27) and the compound (28) in the above Reaction Scheme-10.

The reaction of converting the compound (35) wherein R²⁴ is a lower alkoxy group into the compound (23a) is carried out under the same conditions as those in the reaction of converting the compound (29) wherein R²⁴ is a lower alkoxy group into the compound (30) in the above Reaction Scheme-10.

The reaction of converting the compound (35) wherein R²⁴ is a phenyl-lower alkoxy group into the compound (23a) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in Reaction Scheme-13, which is described hereinbelow.

The starting compound (5) is prepared by the following processes. ##STR135## wherein R¹², R¹³ are the same as defined above, R^(17a) is the same groups for R¹⁷ having at least one oxo group on the heterocyclic group, R^(17b) is the same groups for R¹⁷ having at least one group: --N--R¹² R¹³ (R¹² and R¹³ are the same as defined above) on the heterocyclic group, and R²⁵ is a phenyl-lower alkyl group.

The reaction of the compound (5a) and the compound (36) is carried out in the presence of a reducing agent in a suitable solvent or without a solvent. The solvent may be, for example, water, alcohols (e.g., methanol, ethanol, isopropanol, etc.), acetonitrile, formic acid, acetic acid, ethers (e.g., dioxane, diethyl ether, diglyme, tetrahydrorfuran, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), or a mixture of these solvents. The reducing agent may be, for example, formic acid, an alkali metal salt of fatty acid (e.g., sodium formate, etc.), hydrogenating agent (e.g., sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, etc.), catalysts (e.g., palladium-black, palladium-carbon, platinum oxide, platinum black, Raney-nickel, etc.).

When formic acid is used as a reducing agent, the reaction is usually carried out at room temperature to about 200° C., preferably at 50 to 150° C., for one to about 10 hours. The formic acid is used in an excess amount to the amount of the compound (5a).

When a hydrogenating agent is used as a reducing agent, the reaction is usually carried out at -30° C. to about 100° C., preferably at 0° C. to 70° C., for 30 minutes to about 12 hours. The hydrogenating agent is used in an amount of 1 to 20 moles, preferably in an amount of 1 to 6 moles, to 1 mole of the compound (5a). Especially, when lithium aluminum hydride is used as a hydrogenating agent, the solvent may be ethers (e.g., diethyl ether, dioxane, tetrahydrofuran, diglyme, etc.), or aromatic hydrogen carbonates (e.g., benzene, toluene, xylene, etc.).

When a catalyst is used as a reducing agent, the reaction is usually carried out under a pressure of atmospheric pressure to 20 aims, preferably under atmospheric pressure to 10 atom of hydrogen gas, in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, hydrazine hydrate, etc. at a temperature of -30° C. to about 100° C., preferably at a temperature of 0° C. to 60° C., for about one to 12 hours. The catalyst is used in an amount of 0.1 to 40% by weight, preferably in an amount of 0.1 to 20% by weight, to the weight of the compound (5a).

The compound (36) is usually used at least in an equimolar amount, preferably in an amount of 1 to 3 moles, to 1 mole of the compound (5a).

The reaction of converting the compound (5b) into the compound (5c) is carried out by hydrogenation in the presence of a catalyst in a suitable solvent. The solvent may be, for example, water, acetic acid, alcohols (e.g., methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g., hexane, cyclohexane, etc.), ethers (e.g., dioxane, tetrahydrorfuran, diethyl ether, ethylene glycol dimethyl ether, etc.), esters (e.g., ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g., dimethylformamide, etc.), or a mixture of these solvents. The catalyst may be, for example, palladium. palladium black, palladium hydroxide, palladium hydroxide-carbon, palladium-carbon, platinum, platinum oxide, copper cromite, Raney nickel, etc. The catalyst is used usually in an amount of 0.02 to 1 time of the amount of the compound (5b). The reaction is usually carried out at a temperature of -20° C. to about 100° C., preferably at a temperature of 0° C. to about 70° C., under 1 to 10 atms of hydrogen gas, for about 0.5 to about 20 hours. ##STR136## wherein R¹², R¹³ and R²⁵ are the same as defined above, R^(17c) is the same groups for R¹⁷ but having at least one carboxyl group on the heterocyclic group, R^(17d) is the same groups for R¹⁷ but having at least one --CONR¹² R¹³ (R¹² and R¹³ are the same as defined above) on the heterocyclic group, and R^(17e) is the same groups for R¹⁷ but having at least one --CH₂ NR¹² R¹³ (R¹² and R¹³ are the same as defined above) on the heterocyclic group.

The reaction of the compound (5d) and the compound (36) is carried out under the same conditions as those in the reaction of the compound (1b) and the compound (5) in the above Reaction Scheme-2.

The reactions of converting the compound (5e) into the compound (5f), and converting the compound (5g) into the compound (5h), are carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in the above Reaction Scheme-13.

The reaction of converting the compound (5e) into the compound (5g) is carried out by reduction with using a hydrogenation agent. The hydrogenation agent may be, for example, lithium aluminum hydride, sodium borohydride, diboran, etc., and is used at least in an equimolar amount, preferably in an amount of 1 to 15 moles, to 1 mole of the starting compound. The reduction is carried out in a suitable solvent such as water, a lower alcohol (e.g., methanol, ethanol, isopropanol, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, etc.), or a mixture of these solvents. The reaction is usually carried out at a temperature of -60° C. top 150° C., preferably at a temperature of -30° C. to 100° C., for about 10 minutes to 5 hours. When lithium aluminum hydride or diboran is used as a hydrogenating agent, an anhydrous solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, etc. may be preferably used. ##STR137## wherein R¹², R¹³ and R²⁵ are the same as defined above, R^(17f) is the same groups for R¹⁷ but having at least one halogen-substituted lower alkyl group on the heterocyclic group, and R^(17g) is the same groups for R¹⁷ but having at least one --B'--NR¹² R¹³ (B' is a lower alkylene group, R¹², R¹³ are the same as defined above) on the heterocyclic group.

The reaction of the compound (5i) and the compound (36) is carried out under the same conditions as those in the reaction of the compound (1i) and the compound (22) in the above Reaction Scheme-6.

The reaction of converting the compound (5j) into the compound (5k) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in the above Reaction Scheme-13.

The compound of the formula (1) wherein R⁶ is a group of the formula: ##STR138## wherein R^(11b), p and R^(11a) are the same as defined above, and showing a trans-configuration at the double bond of the above formula may be isomerized into a cis-compound at the corresponding double bond by being exposed to sunlight, a suitable solvent. The solvent may be the same solvents used in the reaction of the carboxylic halide and the amine compound (5) in the reactions of the compound (1b) and the compound (5) in the above Reaction Scheme-2. The reaction is carried out at a temperature of 0° C. to 70° C., preferably at 0° C. to room temperature, for about 1 to 10 hours.

Among the starting compounds (32) used in the Reaction Scheme-11, some compounds (32) are prepared by the following process. ##STR139## wherein R⁵, m, A', M and R²⁴ are the same as defined above, and R²⁶ and R²⁷ are the same or different and each are a lower alkyl group.

The compound of converting the compound (37) into the compound (38) is carried out in the presence of a basic compound in a suitable solvent. The solvent may be, for example, water, lower alcohols (e.g., methanol, ethanol, isopropanol, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), ethers (e.g., dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), or a mixture of these solvents. The basic compound may be, for example, an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), or an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, etc.), etc. The reaction is usually carried out at room temperature to about 200° C., preferably at room temperature to about 150° C., for about 10 minutes to about 25 hours.

The reaction of the compound (38) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (27) and the compound (28) in the above Reaction Scheme-10.

The each step of the above Reaction Scheme-16 can be carried out in one-pot system without isolating the compound (38) from the reaction system. ##STR140## wherein R¹, R², R⁴, R⁵, R⁶, s, T, u, q, Z and A are the same as defined above, R^(5e) is a lower alkenyloxy group, and R^(5f) is a hydroxy group.

The reaction of converting the compound (1o) into the compound (1p) is carried out in the presence of a catalyst and an acid in a suitable solvent. The solvent may be, for example, water, acetic acid, alcohols (e.g., methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g., hexane, cyclohexane, etc.), ethers (e.g., dioxane, tetrahydrorfuran, diethyl ether, ethylene glycol dimethyl ether, etc.), esters (e.g., ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g., dimethylformamide, etc.), or a mixture of these solvents. The catalyst may be, for example, palladium, palladium black, palladium hydroxide, palladium hydroxide-carbon, palladium-carbon, platinum, platinum oxide, copper cromite, Raney nickel, etc. The acid includes, for example, organic acids such as p-toluene-sulfonic acid, etc. The catalyst is used in an amount of 0.02 to 1 time of the amount of the compound (1o). The acid is usually used in a catalytic amount. The reaction is usually carried out at a temperature of -20° C. to about 150° C., preferably at a temperature of 0° C. to about 120° C., for about 0.5 to about 20 hours. ##STR141## wherein T, u, R¹, R², R⁴, A', Z, R⁵, m, R²¹, R²⁴ and X are the same as defined above.

The reaction of the compound (39) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (1i) and the compound (22) in the above Reaction Scheme-6.

The reaction of converting the compound (40) into the compound (41) is carried out under the same conditions as those in the reaction of converting the compound (16) into the compound (17) in the above Reaction Scheme-5.

The reaction of the compound (41) and the compound (18) is carried out under the same conditions as those in the reaction of the compound (17) and the compound (18) in the above Reaction Scheme-5.

The reaction of converting the compound (42) wherein R²⁴ is a lower alkoxy group into the compound (43) is carried out under the same conditions as those in the reaction of converting the compound (1d) into the compound (1e) in the above Reaction Scheme-4.

The reaction of converting the compound (42) wherein R²⁴ is a phenyl-lower alkoxy group into the compound (43) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in the above Reaction Scheme-13.

The reaction of the compound (43) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (1b) and the compound (5) in the above Reaction Scheme-2.

The reaction of the compound (19a) and the compound (44) is carried out in a suitable solvent in the presence of a basic compound, at 0° C. to 150° C., preferably at room temperature to about 100° C., for about 0.5 to 8 hours. The solvent may be any solvent which does not disturb the reaction, and may be water, alcohols (e.g., methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, diglyme, monoglyme, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.), polar solvents (e.g., dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), or a mixture of these solvents. The compound (44) is usually used at least in an equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (19a). The basic compound may be the same basic compounds which are used in the reaction of the compound (6) and the compound (7) in the above Reaction Scheme-3. The starting compound (9) can be prepared, for example, by the process in Reaction Scheme-19 or -20, as explained below. ##STR142## wherein T, u, R¹, R², R⁴, A', Z, R⁵, m, X, R²⁴ and R¹⁹ are the same as defined above.

The reaction of the compound (45) and the compound (28) is carried out under the same conditions as those in the reaction of the compound (1i) and the compound (22) in the above Reaction Scheme-6.

The reaction of converting the compound (46) wherein R²⁴ is a lower alkoxy group into the compound (47) is carried out under the same conditions as those in the reaction of converting the compound (1d) into the compound (1e) in the above Reaction Scheme-4.

The reaction of converting the compound (46) wherein R²⁴ is a phenyl-lower alkoxy group into the compound (47) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in the above Reaction Scheme-13.

The reaction of the compound (47) and the compound (24) is carried out under the same conditions as those in the reaction of the compound (1b) and the compound (5) in the above Reaction Scheme-2. ##STR143## wherein R¹⁹, R⁵ and m are the same as defined above, R^(19a) is a lower alkoxy group.

The reaction of the compound (48) and the compound (49) is carried out in a suitable solvent in the presence of a basic compound. The solvents and the basic compounds are the same ones which are used in the reaction of the compound (6) and the compound (7) in the above Reaction Scheme-3. The compound (49) is usually used at least in an equimolar amount, preferably in an amount of 1 to 3 moles, to 1 mole of the compound (48). The reaction is usually carried out at room temperature to 200° C., preferably at room temperature to about 150° C., for about 1 to about 60 hours.

The reaction of converting the compound (50) into the compound (9b) is carried out under the same conditions as those in the reaction of converting the compound (5b) into the compound (5c) in the above Reaction Scheme-13.

The reaction of the compound (51) and the compound (52) is carried out in a suitable solvent in the presence of a basic compound and a catalyst. The solvent includes, for example, ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g., n-hexane, heptane, cyclo-hexane, etc.), dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, or a mixture of these solvents. The basic compound may be the same ones which are used in the reaction of the compound (1b) and the compound (5) using a carboxylic halide in the above Reaction Scheme-2. The catalyst includes, for example, palladium chloride, tetrakis(triphenylphosphine)palladium, palladium acetate, 1,3-bis(diphenylphosphino)propane, or a mixture of these solvents. The reaction is usually carried out at 0° C. to 200° C., preferably at room temperature to about 150° C., for about 1 to about 20 hours. The compound (52) is usually used at least in an equimolar amount, preferably in an amount of 1 to 10 moles, to 1 mole of the compound (51), The basic compound is usually used at least in an equimolar amount, preferably in an amount of 1 to 3 moles, to 1 mole of the compound (51). The catalyst is used at least in an excess amount of the compound (51).

The reaction of converting the compound (53) into the compound (50) is carried out under the same conditions as those in the reaction of converting the compound (1d) into the compound (1e) in the above Reaction Scheme-4. ##STR144## wherein T, u, R⁵, q, R¹⁸, R¹, R², R⁴, A, Z, s and W are the same as defined above, R^(5q) is an amino group having optionally a lower alkyl substituent, and a group: --C(O)CH₂ --P(O)(R¹⁸)₂ and a group: --R^(5q) are positioned each other at ortho-position.

The reaction of the compound (10a) and the compound (44) is carried out under the same conditions as those in the reaction of the compound (10) and the compound (12) in the above Reaction Scheme-3.

The compound (1r) wherein W is a group of the formula: ##STR145## wherein R^(29b) and X⁻ are the same as defined above) can be obtained by treating with a hydrohalogenic acid such as hydrochloric acid, hydrobromic acid, etc., after the reaction is complete. ##STR146## wherein R¹, R², T, u, R⁴ R¹⁶, R¹⁸ and R²² are the same as defined above.

The reaction of the compound (54) and the compound (12) is carried out under the same conditions as those in the reaction of the compound (10) and the compound (12) in the above Reaction Scheme-3.

The reaction of converting the compound (1s) wherein R¹⁶ is a lower alkoxy group into the compound (1t) is carried out under the same conditions as those in the reaction of converting the compound (1d) into the compound (1e) in the above Reaction Scheme-4.

The reaction of the compound (54) and the compound (20) is carried out under the same conditions as those in the reaction of the compound (10) and the compound (20) in the above Reaction Scheme-3.

The starting compound (54) is prepared, for example, by the following process. ##STR147## wherein R¹, R², M, R¹⁹ and R¹⁸ are the same as defined above.

The halogenation reaction of the compound (58) is carried out under conventional halogenation conditions which are employed in the halogenation reaction of a carboxylic acid. The reaction of the carboxylic acid halide compound of the compound (58) and the compound (55) is carried out in the presence or absence of a basic compound in a suitable solvent. The solvent includes, for example, halogenated hydrocarbons (e.g., methylene chloride, chloroform, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), alcohols (e.g., methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve, methylcellosolve, et.), pyridine, acetone, acetonitrile, water, or a mixture of these solvents. The basic compound includes, for example, organic basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, DBN, DBU, DABCO, etc., or inorganic basic compounds such as potassium carbonate, sodium carbonate, potassium hydride, sodium hydride, potassium hydroxide, sodium hydroxide, silver carbonate, sodium methoxide, sodium ethoxide, etc. The compound (55) is used at least in an equimolar amount, preferably in an amount of 1 to 3 moles, to 1 mole of the carboxylic acid halide compound of the compound (58). The reaction is usually carried out at -30° C. to about 180° C., preferably at 0° C. to about 150° C., for about 5 minutes to about 30 hours.

The reaction of the compound (58a) and the compound (56) is carried out in a suitable solvent, or without a solvent, at 0° C. to about 200° C., preferably at room temperature to about 150° C. The solvent may be the same solvents used in the above reaction of the carboxylic halide of the compound (58) and the compound (55). The compound (56) is used at least in an equimolar amount, preferably in an amount of 1 to 1.5 mole, to 1 mole of the compound (58a). The reaction is carried out for about 1 hour to about 5 hours.

The reaction of the compound (58b) and the compound (7) is carried out under the same conditions as those in the reaction of the compound (9) and the compound (7) in the above Reaction Scheme-3. ##STR148## wherein R¹, R², R⁴, R^(11b), T, u and R¹⁷ are the same as defined above.

The reaction of the compound (1u) and the compound (5) is carried out under the same conditions as those in the reaction of the compound (1b) and the compound (5) in the above Reaction Scheme-2. The starting compound (24) can be prepared, for example, by the method of Reaction Scheme-25, as explained below. ##STR149## wherein R¹, R², M, X and T are the same as defined above, and R³⁰ is a lower alkylsulfonyl group.

The reaction of the compound (59) and the compound (60) is carried out under the same conditions as those in the reaction of the compound (1i) and the compound (22) in the above Reaction Scheme-6. The reaction of the compound (61) and the compound (62) is carried out under the same conditions as those in the reaction of the compound (1i) and the compound (22) in the above Reaction Scheme-6.

The reaction of converting the compound (63) into the compound (24a) is carried out by treating the compound (63) with hydrazine in a suitable solvent, or hydrolyzing the compound (63). The solvent used in the reaction with hydrazine may be, in addition to water, the same solvents used in the reaction using a carboxylic acid halide in the reaction of the compound (1b) and the compound (5) in Reaction Scheme-2. The reaction is usually carried out at room temperature to about 120° C., preferably at 0° C. to about 100° C., for about 0.5 hour to about 5 hours. The hydrazine is usually used at least in an equimolar amount, preferably in an amount of 1 to 6 moles, to 1 mole of the compound (63).

The hydrolysis is carried out in a suitable solvent or without a solvent in the presence of an acid or a basic compound. The solvent includes, for example, water, lower alcohols (e.g., methanol, ethanol, isopropanol, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), ethers (e.g., diethyl ether, dioxane, tetra-hydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g., acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g., hydrochloric acid, hydrobromic acid, etc.), organic acids (e.g., formic acid, acetic acid, aromatic sulfonic acids, etc.). The basic compound includes, for example, an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an alkali metal or alkaline earth metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.). The reaction is usually carried out at room temperature to about 200° C., preferably at room temperature to about 150° C., for about 10 minutes to about 25 hours.

Among the desired compounds (1) of the present invention, the compounds having an acidic group can easily be converted into salts by treating them with a pharmaceutically acceptable basic compound. The basic compound includes, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, etc., an alkali metal carbonate such as sodium carbonate, etc., an alkali metal hydrogen carbonate such as potassium hydrogen carbonate, an alkali metal alkoxide such as sodium methylate, potassium ethylate, and the like.

Besides, among the desired compounds (1) of the present invention, the compounds having a basic group can easily be converted into acid addition salts thereof by treating them with a pharmaceutically acceptable acid. The acid includes, for example, inorganic acids (e.g. sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, etc.), and organic acids (e.g. acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, benzoic acid, etc.). These salts can be also used as an active ingredient of the pharmaceutical composition of the present invention as well as the compound (1) in a free form. In addition, the compounds of the present invention also include stereoisomers and optical isomers, and these isomers are also used as an active ingredient.

The desired compound obtained in the above Reaction Schemes can easily be isolated and purified by conventional isolation methods from the reaction system. The isolation methods are, for example, distillation method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, extraction with solvent, dilution method, and the like.

The compounds (1) of the present invention are useful as a protein kinase inhibitor, and can be used in the form of a conventional pharmaceutical preparation. The preparation is prepared by using conventional diluents or carriers such as fillers, thickening agents, binders, wetting agent, disintegrators, surfactants, lubricants, and the like. The pharmaceutical preparations can be selected from various forms in accordance with the desired utilities, and the representative forms are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like. In order to form in tablets, there are used carriers such as vehicles (e.g. lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.), binders (e.g. water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrators (e.g. dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, etc.), disintegration inhibitors (e.g. white sugar, stearin, cacao butter, hydrogenated oils, etc.), absorption promoters (e.g. quaternary ammonium base, sodium laurylsulfate, etc.), wetting agents (e.g. glycerin, starches, etc.), adsorbents (e.g. starches, lactose, kaolin, bentonite, colloidal silicates, etc.), lubricants (e.g. purified talc, stearates, boric acid powder, polyethylene glycol, etc.), and the like. Moreover, the tablets may also be in the form of a conventional coated tablet, such as sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film coating tablets, or double or multiple layer tablets. In the preparation of pills, the carriers may be conventional ones, and include, for example, vehicles (e.g. glucose, lactose, starches, cacao butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (e.g. gum arabic powder, tragacanth powder, gelatin, ethanol, etc.), disintegrators (e.g. laminaran, agar, etc.), and the like. In the preparation of suppositories, the carriers may be conventional ones, and include, for example, polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides, and the like. The capsules are prepared by mixing the active compound with a conventional carrier, and fulfilling the mixture into hard gelatin capsules or soft capsules. In the preparation of injections, the solutions and suspensions are sterilized and are preferably made isotonic with the blood. In the preparation of these solutions, emulsions and suspensions, there are used conventional diluents, such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the pharmaceutical preparations may also be incorporated with sodium chloride, glucose, or glycerin in an amount sufficient to make them isotonic, and may also be incorporated with conventional solubilizers, buffers, anesthetizing agents. Besides, the pharmaceutical preparations may optionally be incorporated with coloring agents, preservatives, perfumes, flavors, sweetening agents, and other medicaments, if required.

The amount of the desired compound (1) of the present invention or a salt thereof to be incorporated into the pharmaceutical preparation is not specified but may be selected from a broad range, but usually, it is preferably in the range of about 1 to 70% by weight, preferably in the range of about 5 to 50% by weight.

The pharmaceutical preparation of the present invention may be administered in any method, and the suitable method for administration may be determined in accordance with various forms of preparations, ages, sexes and other conditions of the patients, the degree of severity of diseases, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are intravenously administered alone or together with a conventional auxiliary liquid (e.g. glucose, amino acid solutions), and further are optionally administered alone in intramuscular, intracutaneous, subcutaneous, or intraperitoneal route, if required. Suppositories are administered in intrarectal route.

The dosage of the pharmaceutical preparation of the present invention may be selected in accordance with the usage, ages, sexes and other conditions of the patients, the degree of severity of the diseases, and the like, but it is usually in the range of about 0.6 to 50 mg of the compound (1) or a salt thereof per 1 kg of body weight of the patient per day. The active compound is contained in an amount of about 10 to 1000 mg per one unit of the dosage form.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated in more detail by the following Preparations of pharmaceutical composition, Reference Examples of processes for preparing the starting compounds to be used for preparing the desired compounds of the present invention, and Examples of processes for preparing the desired compounds, and Experiment of the activities of the desired compounds of the present invention.

Preparation 1

Film coated tablets are prepared from the following components.

    ______________________________________                                         Components                 Amount                                              ______________________________________                                         2-[2-Methoxy-4-{3-[4-(4-methyl-1-piperazinyl)-                                                            150 g                                                 1-piperidinylcarbonyl]acryloyl}phenoxymethyl-                                  carbonylamino]benzothiazole                                                    Avicel (trade mark of microcrystalline cellulose 40 g                          manufactured by Asahi Chemical Industry, Co., Ltd.)                            Corn starch 30 g                                                               Magnesium stearate  2 g                                                        Hydroxypropyl methylcellulose 10 g                                             Polyethylene glycol-6000  3 g                                                  Castor oil 40 g                                                                Ethanol 40 g                                                                 ______________________________________                                    

The active compound of the present invention, Avicel, corn starch and magnesium stearate are mixed and kneaded, and the mixture is tabletted by using a conventional pounder (R 10 mm) for sugar coating. The tablets thus obtained are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil and ethanol to give film coated tablets.

Preparation 2

Tablets are prepared from the following components.

    ______________________________________                                         Components                 Amount                                              ______________________________________                                         2-[3-Methoxy-4-{3-[4-(3,4-dimethyl-1-piperazinyl)-                                                        150 g                                                 1-piperidinylcarbonyl]acryloyl}phenoxymethyl-                                  carbonylamino]benzimidazole                                                    Citric acid 1.0 g                                                              Lactose 33.5 g                                                                 Dicalcium phosphate 70.0 g                                                     Pullonic F-68 30.0 g                                                           Sodium laurylsulfate 15.0 g                                                    Polyvinylpyrrolidone 15.0 g                                                    Polyethylene glycol (Carbowax 1500) 4.5 g                                      Polyethylene glycol (Carbowax 6000) 45.0 g                                     Corn starch 30.0 g                                                             Dry sodium stearate 3.0 g                                                      Dry magnesium stearate 3.0 g                                                   Ethanol q.s.                                                                 ______________________________________                                    

The active compound of the present invention, citric acid, lactose, dicalcium phosphate, Pullonic F-68 and sodium laurylsulfate are mixed.

The mixture is screened with No. 60 screen and is granulated with an alcohol solution containing polyvinylpyrrolidone, Carbowax 1500 and 6000. If required, an alcohol is added thereto so that the powder mixture is made a paste-like mass. Corn starch is added to the mixture and the mixture is continuously mixed to form uniform particles. The resulting particles are passed through No. 10 screen and entered into a tray and then dried in an oven at 100° C. for 12 to 14 hours. The dried particles are screened with No. 16 screen and thereto are added dry sodium laurylsulfate and dry magnesium stearate, and the mixture is tabletted to form the desired shape.

The core tablets thus prepared are vanished and dusted with talc in order to guard from wetting. Undercoating is applied to the core tablets. In order to administer the tablets orally, the core tablets are vanished several times. In order to give round shape and smooth surface to the tablets, further undercoating and coating with lubricant are applied thereto. The tablets are further coated with a coloring coating material until the desired colored tablets are obtained. After drying, the coated tablets are polished to obtain the desired tablets having uniform gloss.

Preparation 3

An injection preparation is prepared from the following components.

    ______________________________________                                         Components                  Amount                                             ______________________________________                                         2-{2-(3-Morpholinopropyl)-4-[3-(4-pyridyl)acryloyl}-                                                       5 g                                                  phenoxymethylcarbonylamino}benzothiazole                                       Polyethylene glycol (molecular weight: 4000) 0.3 g                             Sodium chloride 0.9 g                                                          Polyoxyethylene sorbitan monooleate 0.4 g                                      Sodium metabisulfite 0.1 g                                                     Methyl-paraben 0.18 g                                                          Propyl-paraben 0.02 g                                                          Distilled water for injection 10.0 ml                                        ______________________________________                                    

The above parabens, sodium metabisulfite and sodium chloride are dissolved with stirring in distilled water of half volume of the above at 80° C. The solution thus obtained is cooled to 40° C., and the active compound of the present invention and further polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. To the solution is added distilled water for injection to adjust to the desired volume, and the solution is sterilized by filtering with an appropriate filter paper to give an injection preparation.

Reference Example 1

A solution of o-isopropylphenol (39.5 g), potassium carbonate (40 g) and ethyl α-bromoacetate (40 ml) in dimethylformamide (300 ml) is heated with stirring at 80° C. for 8 hours. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure to remove the solvent. The residue thus obtained is dissolved in a solution of sodium hydroxide (20 g) in water (300 ml) and ethanol (200 ml), and the mixture is refluxed for 1.5 hour. After cooling, the mixture is acidified with conc. hydrochloric acid, and the precipitated crystals are collected by filtration to give α-(2-isopropylphenoxy)acetic acid (37 g).

White powder; ¹ H-NMR (CDCl₃) δppm: 1.24 (6H, d, J=7 Hz), 3.39 (1H, sept, J=7 Hz), 4.69 (2H, s), 6.75 (1H, dd, J=1 Hz, J=8 Hz), 6.95-7.3 (3H, m).

Reference Example 2

A solution of α-(2-isopropylphenoxy)acetic acid (13.1 g) in thionyl chloride (30 ml) is refluxed for 30 minutes. The mixture is concentrated under reduce pressure to remove the excess thionyl chloride, and the resultant is dissolved in dichloromethane (50 ml). The mixture is added dropwise into a solution of 2-aminobenzothiazole (9.1 g) and pyridine (7.2 ml) in dichloromethane (100 ml) under ice-cooling. The mixture is stirred at the same temperature for five hours, and then washed with water, dried, and concentrated under reduced pressure. To the residue is added ethanol to give 2-(2-isopropylphenoxymethylcarbonylamino)benzothiazole (16.66 g).

Yellow powder; ¹ H-NMR (CDCl₃) δppm: 1.32 (6H, d, J=7 Hz) 3.43 (1H, sept, J=7 Hz), 4.78 (2H, s), 6.85 (1H, dd, J=1 Hz, J=8 Hz), 7.0-7.55 (5H, m), 7.8-7.9 (2H, m), 9.74 (1H, br).

Reference Example 3

To a solution of dimethyl methylphosphonate (19.5 ml) in anhydrous tetrahydrofuran (300 ml) is added a 1.72 M solution of n-butyl lithium in n-hexane (107 ml) at -50° C. Thirty minutes later, to the mixture is added in portions 2-(2-methoxy-4-formylphenoxymethylcarbonylamino)benzothiazole (20.5 g) under nitrogen atmosphere. The mixture is stirred at -50° C. for one hour, and thereto is added water. The mixture is acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=200:1→30:1) to give dimethyl {2-[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)phenyl]-2-hydroxyethyl}phosphonate (19.0 g).

¹ H-NMR (CDCl₃) δppm: 2.05-2.35 (2H, m), 3.73, 3.76, 3.78 and 3.81 (6H, each s), 3.98 (2H, d, J=2.5 Hz), 4.01 (3H, s), 4.77 (2H, s), 5.0-5.15 (1H, m), 6.90 (1H, dd, J=2 Hz, J=8 Hz), 6.98 (1H, d, J=8 Hz), 7.07 (1H, d, J=2 Hz), 7.25-7.5 (2H, m), 7.8-7.9 (2H, m), 10.66 (1H, br).

To a solution of dimethyl {2-[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)phenyl]-2-hydroxyethyl}phosphonate (19.0 g) in chloroform (300 ml) is added active manganese dioxide (17.7 g), and the mixture is refluxed for three hours. To the mixture is additionally added active manganese dioxide (18 g), and the mixture is refluxed for three hours. To the mixture is further added active manganese dioxide (20 g), and the mixture is refluxed for three hours. The manganese dioxide is collected by filtration, and washed with chloroform. The filtrate and the washings are combined and concentrated under reduced pressure to remove the chloroform. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=200:1→50:1) to give dimethyl {[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyl}phosphonate (7.76 g).

White powder; ¹ H-NMR (CDCl₃) δppm: 3.62 (2H, d, J=22.5 Hz), 3.79 (6H, d, J=11.2 Hz), 4.04 (3H, s), 4.85 (2H, s), 7.02 (1H, d, J=8.5 Hz), 7.3-7.55 (2H, m), 7.6-7.7 (2H, m), 7.8-7.9 (2H, m), 10.31 (1H, br).

Reference Example 4

To a solution of chloroacetyl chloride (10.0 ml) in anhydrous 1,2-dichloroethane (250 ml) is added aluminum chloride (12 g) at room temperature, and the mixture is stirred for 20 minutes. To the mixture is added at once 2-(2-isopropylphenoxymethylcarbonylamino)benzothiazole (20 g), and the mixture is stirred at room temperature for one hour. The reaction mixture is poured into water, and thereto is added n-hexane. The precipitates are collected by filtration, washed with water, and dried to give 2-[2-isopropyl-4-(2-chloroacetyl)phenoxymethylcarbonylamino]benzothiazole (25.9 g).

White powder; ¹ H-NMR (DMSO-d₆) δppm: 1.24 (6H, d, J=7 Hz), 3.38 (1H, m), 5.12 (4H, s), 7.01 (1H, d, J=9 Hz), 7.25-7.55 (2H, m), 7.7-7.95 (3H, m), 7.97 (1H, d, J=8 Hz), 13.00 (1H, br).

Reference Example 5

A suspension of 2-[2-isopropyl-4-(2-chloroacetyl)phenoxymethylcarbonylamino]benzimidazole (4.0 g) and triphenylphosphine (2.8 g) in chloroform (100 ml) is refluxed for 7 hours. The reaction mixture is concentrated under reduced pressure, and the residue is crystallized from dichloromethane-diethyl ether to give [3-isopropyl-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyltriphenylphosphonium chloride (3.8 g).

¹ H-NMR (DMSO-d₆) δppm: 1.23 (6H, d, J=7 Hz), 3.40 (1H, m), 5.18 (2H, s), 6.19 (2H, d, J=13.5 Hz), 7.09 (1H, d, J=9 Hz), 7.25-7.5 (2H, m), 7.6-8.05 (19H, m), 12.77 (1H, s).

To a solution of [3-isopropyl-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyltriphenylphosphonium chloride (3.3 g) in methanol (50 ml) is added DBU (1 ml), and the mixture is stirred at room temperature for two hours. The precipitated crystals are collected by filtration, washed with methanol, and dried to give [3-isopropyl-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methylenetriphenylphosphorane (2.27 g).

White powder; ¹ H-NMR (CDCl₃) δppm: 1.32 (6H, d, J=7 Hz), 3.42 (1H, sept, J=7 Hz), 4.2-4.6 (1H, m), 4.73 (2H, s), 6.75 (1H, d, =8.5 Hz), 7.25-8.0 (21H, m), 10.01 (1H, br).

Using the suitable starting compounds, the following compound is obtained in the same manner as in Reference Example 5. [3-(3-chloropropyl)-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methylenetriphenylphosphonium chloride:

White powder; ¹ H-NMR (CDCl₃) δppm: 2.11 (2H, tt, J=6.6 Hz, J=8.0 Hz), 2.86 (2H, t, J=8.0 Hz), 3.71 (2H, t, J=6.6 Hz), 5.20 (2H, s), 6.17 (2H, d, J=12.8 Hz), 7.13 (1H, d, J=8.7 Hz), 7.34 (1H, t, J=7.5 Hz), 7.48 (1H, t, J=7.0 Hz), 7.76-8.02 (19H, m), 12.75 (1H, br).

Reference Example 6

To dimethylformamide (200 ml) are added 2-methoxy-4-acetylphenol (20 g), ethyl α-bromoacetate (15 ml) and potassium carbonate (18.3 g), and the mixture is stirred at room temperature overnight. After the reaction is complete, water is added to the mixture, and the mixture is extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The resulting crystals are collected, and washed with n-hexane-diethyl ether to give ethyl α-(2-methoxy-4-acetylphenoxy)acetate (23.86 g).

To chloroform (230 ml) are added ethyl α-(2-methoxy-4-acetylphenoxy)acetate (23 g) and copper (II) bromide (55 g), and the mixture is refluxed for 3.5 hours. After the reaction is complete, the mixture is filtered through a cerite pad to remove the precipitates, and washed with sodium hypochlorite. The filtrate is dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent, and then crystallized to give ethyl α-[2-methoxy-4-(2-bromoacetyl)phenoxy]acetate (21.28 g).

To chloroform (200 ml) are added ethyl α-[2-methoxy-4-(2-bromoacetyl)phenoxy]acetate (20 g) and triphenylphosphine (20.6 g) in an ice-bath, and the mixture is stirred for one hour. After confirming that the starting compounds are well consumed, the mixture is washed with an aqueous potassium carbonate solution. The mixture is dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. To the residue is added methanol (200 ml), and thereto is added dropwise sodium hydroxide in an ice-bath. After confirming that the starting compounds are well consumed, to the mixture is added conc hydrochloric acid. The precipitated crystals are washed with water and diethyl ether, and dried to give (3-methoxy-4-carboxymethoxybenzoyl)methylenetriphenylphosphorane (25 g).

To dichloromethane (50 ml) are added (3-methoxy-4-carboxymethoxybenzoyl)methylenetriphenylphosphorane (5 g), 2-aminobenzothiazole (1.9 g), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.93 g) and triethylamine (3.3 ml), and the mixture is stirred overnight. After the reaction is complete, the mixture is washed with an aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate to remove the solvent, and further recrystallized from toluene to give [3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methylenetriphenylphosphorane (5.17 g).

Pale yellow powder; ¹ H-NMR (CDCl₃) δppm: 4.03 (3H, s), 4.12-4.62 (1H, m), 4.79 (2H, s), 6.96 (1H, d, J=8.3 Hz), 7.25-7.90 (22H, m).

Reference Example 7

To a solution of N-benzyl-4-piperidone (8.0 g) and 3,4-dimethylpiperazine (9.5 g) in ethanol (100 ml) are added 5% platinum-carbon (2 g) and acetic acid (14.4 ml), and the mixture is subjected to catalytic hydrogenation at room temperature under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. Water is added to the resultant, and the mixture is basified with a 5% aqueous sodium hydroxide solution, and the mixture is extracted with diethyl ether. The extract is washed with water, dried and concentrated under reduced pressure to remove the solvent. The residue is dissolved in ethanol, and thereto is added to conc. hydrochloric acid to give a hydrochloride. The resulting white powder is collected by filtration, dissolved in water, and basified with a 5% aqueous sodium hydroxide solution. The mixture is extracted with diethyl ether, washed with water, dried, and concentrated under reduced pressure to give 4-(3,4-dimethyl-1-piperazinyl)-1-benzylpiperidine (4.2 g).

¹ H-NMR (CDCl₃) δppm: 1.04 (3H, d, J=6 Hz), 1.45-2.5 (12H, m), 2.27 (3H, s), 2.7-3.05 (4H, m), 3.48 (2H, s), 7.31 (5H, m).

To a solution of 4-(3,4-dimethyl-1-piperazinyl)-1-benzylpiperidine (4.2 g) in ethanol (50 ml) is added 20% palladium hydroxide-carbon (0.4 g), and the mixture is subjected to catalytic hydrogenation at 50° C. under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is evaporated to give 4-(3,4-dimethyl-1-piperazinyl)piperidine (1.65 g).

Colorless oil; b.p. 145° C. (0.3 mmHg); ¹ H-NMR (CDCl₃) δppm: 1.05 (3H, d, J=6 Hz), 1.25-1.55 (2H, m), 1.75-3.3 (14H, m), 2.31 (3H, s).

Reference Example 8

A solution of 1-benzyl-L-proline (50 g) in dichloromethane (300 ml) is cooled with ice. To the solution is added N-methylmorpholine (22.5 g), and then further thereto is added dropwise isobutyl chloroformate (30 g). The mixture is stirred at the same temperature for about one hour, and thereto is added dropwise pyrrolidine (18.8 ml) at the same temperature. The mixture is warmed to room temperature, and stirred for two days. The mixture is washed twice with water (250 ml), and dried over magnesium sulfate. The mixture is concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate-n-hexane to give 2-(1-pyrrolidinyl)carbonyl-1-benzylpyrrolidine (31 g), as white powder.

In ethanol (300 ml) is suspended 5% palladium-carbon (3 g), and thereto is added 2-(1-pyrrolidinyl)carbonyl-1-benzylpyrrolidine (30 g), and the mixture is subjected to catalytic hydrogenation at room temperature under atmospheric pressure. The mixture is filtered, and the filtrate is concentrated under reduced pressure to remove the solvent to give 2-(1-pyrrolidinyl)carbonylpyrrolidine (about 18 g) as an oily product.

Lithium aluminum hydride (9 g) is suspended in dry tetrahydrofuran (100 ml) under ice-cooling, and thereto is added dropwise a solution of 2-(1-pyrrolidinyl)carbonylpyrrolidine (33 g) in dry tetrahydrofuran (80 ml). The mixture is refluxed under nitrogen atmosphere for four hours. The mixture is cooled with ice, and thereto is added a saturated aqueous sodium sulfate solution (about 15 ml), and then mixture is further stirred at room temperature for three hours. The precipitated sodium sulfate is removed by filtration, washed well with chloroform. The filtrate and the washings are combined, concentrated under reduced pressure, and evaporated to give 2-(1-pyrrolidinyl)methylpyrrolidine (22 g).

Colorless oil; B.p. 99-101° C. (20 mmHg).

Reference Example 9

4-Benzyl-2-chloromethylmorpholine (15 g) and 4-(2-hydroxyethyl)piperazine (25 ml) are mixed, and the mixture is heated with stirring at 130° C. for five hours. After the reaction is complete, the mixture is extracted with chloroform, and the extract is dried over magnesium sulfate. The residue thus obtained is concentrated under reduced pressure to give 4-benzyl-2-[4-(2-hydroxyethyl)-1-piperazinyl]methylmorpholine (16 g).

¹ H-NMR (CDCl₃) δppm: 1.86 (1H, t, J=10.6 Hz), 2.07-2.27 (2H, m), 2.37-3.05 (14H, m), 3.49 (2H, d, J=2.3 Hz), 3.57-3.89 (5H, m), 7.24-7.33 (5H, m).

4-Benzyl-2-[4-(2-hydroxyethyl)-1-piperazinyl]methylmorpholine (16 g) is dissolved in ethanol (160 ml), and thereto is added palladium hydroxide (1.6 g). The mixture is subjected to de-benzylation at 50° C. under hydrogen atmosphere. Five hours later, the mixture is filtered through a cerite pad, and the filtrate is concentrated under reduced pressure. The resulting crystals are washed with diethyl ether-n-hexane to give 2-[4-(2-hydroxyethyl)-1-piperazinyl]methylmorpholine (9.09 g).

M.p. 73-75.5° C.; White powder; ¹ H-NMR (CDCl₃) δppm: 2.25 (1H, dd, J=4.2 Hz, J=13.0 Hz), 2.37-2.74 (11H, m), 2.74-3.02 (6H, m), 3.49-3.77 (4H, m), 3.85-3.93 (1H, m).

Using the suitable starting compounds, the compounds as listed in Tables 1 to 4 are obtained in the same manner as in Reference Example 1.

                                      TABLE 1                                      __________________________________________________________________________      ##STR150##                                                                    __________________________________________________________________________     Reference Example 10                                                             R.sup.5 : CH.sub.3 (2-position) m: 1 A: --CH.sub.2 --                          Crystalline form: white powder Form: Free NMR (1)                              Reference Example 11                                                           R.sup.5 : C.sub.2 H.sub.5 (2-position) m: 1 A: --CH.sub.2 --                   Crystalline form: White powder Form: Free NMR (2)                              Reference Example 12                                                           R.sup.5 : --(CH.sub.2).sub.2 CH.sub.3 (2-position) m: 1 A --CH.sub.2 --        Crystalline form: White powder Form: Free NMR (3)                              Reference Example 13                                                           R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (2-position) m: 1 A: --CH.sub.2                                   --                                                  M.p. 102-104° C.                                                                        Solvent for recrystallization: Ethanol-water                     Crystalline form: White powder Form: Free                                    __________________________________________________________________________

                  TABLE 2                                                          ______________________________________                                         Reference Example 14                                                             R.sup.5 : --(CH.sub.2).sub.4 CH.sub.3 (2-position)                             m: 1                                                                           A: --CH.sub.2 --                                                               M.p. 71.4-74.4° C.                                                      Solvent for recrystallization: Ethanol-water                                   Crystalline form: White powder                                                 Form: Free                                                                     Reference Example 15                                                           R.sup.5 : F (2-position)                                                       m: 1                                                                           A: --CH.sub.2 --                                                               Crystalline form: White powder                                                 Form: Free                                                                     NMR (4)                                                                        Reference Example 16                                                           R.sup.5 : Cl (2-position)                                                      m: 1                                                                           A: --CH.sub.2 --                                                               Crystalline form: White powder                                                 Form: Free                                                                     NMR (5)                                                                        Reference Example 17                                                           R.sup.5 : --(CH.sub.2).sub.4 -- (combined at 2- and 3-positions)              m: 2                                                                           A: --CH.sub.2 --                                                               Crystalline form: white powder                                                 Form: Free                                                                     NMR (6)                                                                        Reference Example 18                                                           R.sup.5 : CH.sub.3 (2- and 3-positions)                                        m: 2                                                                           A: --CH.sub.2 --                                                               Crystalline form: White powder                                                 Form: Free                                                                     NMR (7)                                                                       ______________________________________                                    

                  TABLE 3                                                          ______________________________________                                         Reference Example 19                                                            R.sup.5 : CH.sub.3 (2- and 6-positions)                                        m: 2                                                                           A: --CH.sub.2 --                                                               Crystalline form: Yellow powder                                                Form: Free                                                                     NMR (8)                                                                        Reference Example 20                                                           R.sup.5 : CH.sub.3 (3- and 5-positions)                                        m: 2                                                                           A : --CH.sub.2 --                                                              Crystalline form: White powder                                                 Form: Free                                                                     NMR (9)                                                                        Reference Example 21                                                           R.sup.5 : CH.sub.3 (3-position)                                                m: 1                                                                           A: --CH.sub.2 --                                                               Crystalline form: White powder                                                 Form: Free                                                                     NMR (10)                                                                       Reference Example 22                                                           R.sup.5 : C.sub.2 H.sub.5 (3-position)                                         m: 1                                                                           A: --CH.sub.2 --                                                               M.p. 102-104° C.                                                        Solvent for recrystallization: Ethanol-water                                   Crystalline form: White powder                                                 Form: Free                                                                     Reference Example 23                                                           R.sup.5 : --(CH.sub.2).sub.2 CH.sub.3 (3-position)                             m: 1                                                                           A: --CH.sub.2 --                                                               M.p. 63.5-66.0° C.                                                      Solvent for recrystallization: Ethanol-water                                   Crystalline form: White powder                                                 Form: Free                                                                    ______________________________________                                    

                                      TABLE 4                                      __________________________________________________________________________     Reference Example 24                                                                                       R                                                                             .sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (3-positio                                n) m: 1 A: --CH.sub.2 --                            M.p. 69.0-72.5° C.                                                                      Solvent for recrystallization: Ethanol-water                   Crystalline form: Colorless prisms                                                             Form: Free NMR (11)                                              Reference Example 25                                                            -                                                                                                        m: 1 A: --CH.sub.2 --                                - Crystalline form: white solid Form: Free NMR (12)                           Reference Example 26                                                           R.sup.5 : Cl (3-position) m: 1 A:  --CH.sub.2 --                               Crystalline form: White powder Form: Free NMR (13)                             Reference Example 27                                                           R.sup.5 : F (3-position) m: 1 A: --CH.sub.2 --                                 Crystalline form: White powder Form: Free NMR (14)                             Reference Example 28                                                           R.sup.5 : CH.sub.3 O (3-position) m: 1 A --CH.sub.2 --                         Crystalline form: Beige powder Form: Free NMR (15)                             Reference Example 29                                                           R.sup.5 : C.sub.2 H.sub.5 O (3-position) m: 1 A: --CH.sub.2 --                 Crystalline form: Beige powder Form: Free NMR (16)                           __________________________________________________________________________

¹ H-NMR spectrum (NMR (1) to NMR (17)) as described in Tables 1 to 4 are as follows:

NMR (1) (DMSO-d₆) δppm: 2.19 (3H, s), 4.68 (2H, s), 6.83 (2H, dd, J=7.8 Hz, J=13.2 Hz), 7.12 (2H, t, J=7.8 Hz), 12.96 (1H, s); NMR (2) (DMSO-d₆) δppm: 1.14 (3H, t, J=7.5 Hz), 2.61 (2H, q, J=7.5 Hz), 4.69 (2H, s), 6.78-6.95 (2H, m), 7.05-7.20 (2H, m), 12.97 (1H, s); NMR (3) (CDCl₃) δppm: 0.95 (3H, t, J=7.4 Hz), 1.5-1.8 (2H, m), 2.65 (2H, t, J=7.4 Hz), 4.65 (2H, s), 6.73 (1H, d, J=8.3 Hz), 6.9-7.05 (1H, m), 7.15 (2H, t, J=7.2 Hz), 9.4-10.1 (1H, m); NMR (4) (DMSO-d₆) δppm: 4.77 (2H, s), 6.88-7.30 (4H, m), 13.09 (1H, s); NMR (5) (CDCl₃) δppm: 4.76 (2H, s), 6.89 (1H, dd, J=1.5 Hz, J=8.0 Hz), 6.99 (1H, dt, J=1.5 Hz, J=7.6 Hz), 7.23 (1H, dt, J=1.5 Hz, J=7.6 Hz), 7.41 (1H, dd, J=1.5 Hz, J=8.0 Hz), 8.16 (1H, br); NMR (6) (DMSO-d₆) δppm: 1.6-1.85 (4H, m), 2.55-2.75 (4H, m), 4.63 (2H, s), 6.57 (1H, d, J=8 Hz), 6.65 (1H, d, J=7.5 Hz), 6.9-7.05 (1H, m), 12.94 (1H, br); NMR (7) (DMSO-d₆) δppm: 2.10 (3H, s), 2.20 (3H, s), 4.63 (2H, s), 6.64 (1H, d, J=8 Hz), 6.75 (1H, d, J=7.5 Hz), 6.95-7.1 (1H, m), 12.9 (1H, br); NMR (8) DMSO-d₆) δppm: 2.22 (6H, s), 4.35 (2H, s), 6.87-7.06 (3H, m), 12.87 (1H, s); NMR (9) (DMSO-d₆) δppm: 2.22 (6H, s), 4.48 (2H, s), 6.48 (2H, s), 6.60 (1H, s); NMR (10) (DMSO-d₆) δppm: 2.26 (3H, s), 4.62 (2H, s), 6.60-6.80 (3H, m), 7.11-7.18 (1H, m); NMR (11) (DMSO-d₆) δppm: 0.85 (3H, t, J=7.2 Hz), 1.17-1.38 (2H, m), 1.45-1.60 (2H, m), 2.49-2.57 (2H, m), 4.63 (2H, s), 6.66-6.79 (3H, m), 7.13-7.21 (1H, m), 13.00 (1H, br); NMR (12) (CDCl₃) δppm: 1.22 (6H, d, J=6.9 Hz), 2.77-3.00 (1H, m), 4.68 (2H, s), 6.66-6.76 (1H, m), 6.81-6.95 (2H, m), 7.17-7.29 (1H, m), 8.65 (1H, brs); NMR (13) (CDCl₃) δppm: 4.69 (2H, s), 6.79-6.85 (1H, m), 6.85-7.04 (2H, m), 7.19-7.28 (1H, m), 8.00 (1H, br); NMR (14) (CDCl₃) δppm: 4.69 (2H, s), 6.62-6.79 (3H, m), 7.20-7.32 (1H, m), 9.07 (1H, br); NMR (15) (CDCl₃) δppm: 3.79 (3H, s), 4.67 (2H, s), 6.47-6.61 (3H, m), 7.16-7.26 (1H, m), 9.12 (1H, br); NMR (16) (CDCl₃) δppm: 1.40 (3H, t, J=7.0 Hz), 4.01 (2H, q, J=7.0 Hz), 4.66 (2H, s), 6.45-6.62 (3H, m), 7.13-7.25 (1H, m), 8.34 (1H, br).

Using the suitable starting compounds, the compounds as listed in Tables 5-9 are obtained in the same manner as Reference Example 2.

                  TABLE 5                                                          ______________________________________                                          ##STR152##                                                                    ______________________________________                                         Reference Example 30                                                             R.sup.5 : CH.sub.3 (2-position) m: 1 A: --CH.sub.2 -- R.sup.4 : H                                                Crystalline form: Yellow powder                                               Form: Free NMR (1)                            Reference Example 31                                                           R.sup.5 : C.sub.2 H.sub.5 (2-position) m: 1 A: --CH.sub.2 -- R.sup.4 :                                          H                                             Crystalline form: Pale yellow powder  Form: Free NMR (2)                       Reference Example 32                                                           R.sup.5 : --(CH.sub.2).sub.2 CH.sub.3 (2-position) m: 1 A: --CH.sub.2                                           -- R.sup.4 : H                                Crystalline form: Yellow powder  Form: Free NMR (3)                            Reference Example 33                                                           R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (2-position) m: 1 A: --CH.sub.2                                           -- R.sup.4 : H                              Crystalline form: Yellow solid                                                                   Form: Free   NMR (4)                                         ______________________________________                                    

                  TABLE 6                                                          ______________________________________                                         Reference Example 34                                                             R.sup.5 : H (2-position)                                                       m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Pale yellow powder                                           Form: Free                                                                     NMR (5)                                                                        Reference Example 35                                                           R.sup.5 : --(CH.sub.2).sub.4 CH.sub.3 (2-position)                             m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Yellow powder                                                Form: Free                                                                     NMR (6)                                                                        Solvent for recrystallization: Ethyl acetate-n-hexane                          Reference Example 36                                                           R.sup.5 : F (2-position)                                                       m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Pale yellow powder                                           Form: Free                                                                     NMR (7)                                                                        Reference Example 37                                                           R.sup.5 : Cl (2-position)                                                      m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Yellow powder                                                Form: Free                                                                     NMR (8)                                                                        Reference Example 38                                                           R.sup.5 : --(CH.sub.2).sub.4 -- (combined at 2- and 3-positions)              m: 2                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: White powder                                                 Form: Free                                                                     NMR (9)                                                                       ______________________________________                                    

                  TABLE 7                                                          ______________________________________                                                 Reference Example 39                                                            R.sup.5 : CH.sub.3 (2- and 3-positions)                                 m: 2                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Yellow powder                                                Form: Free                                                                     NMR (10)                                                                       Reference Example 40                                                           R.sup.5 : CH.sub.3 (2- and 6-positions)                                        m: 2                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Yellow powder                                                Form: Free                                                                     NMR (11)                                                                       Reference Example 41                                                           R.sup.5 : CH.sub.3 (3- and 5-positions)                                        m: 2                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: White powder                                                 Form: Free                                                                     NMR (12)                                                                       Reference Example 42                                                           R.sup.5 : --(CH.sub.2).sub.3 Cl (2-position)                                   m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Yellow powder                                                Form: Free                                                                     NMR (13)                                                                       Reference Example 43                                                           R.sup.5 : --(CH.sub.2).sub.2 Cl (2-position)                                   m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: White powder                                                 Form: Free                                                                     NMR (14)                                                                     ______________________________________                                    

                                      TABLE 8                                      __________________________________________________________________________     Reference Example 44                                                             R.sup.5 : CH.sub.3 (3-position) m: 1 A: --CH.sub.2 -- R.sup.4 : H            Solvent for recrystailization: Ethyl acetate-n-hexane                          Crystalline form: Pale brown powder                                                                 Form: Free                                                                              NMR (15)                                           Reference Example 45                                                           R.sup.5 : C.sub.2 H.sub.5 (3-position) m: 1 A: --CH.sub.2 -- R.sup.4 :                                     H                                                  Crystalline form: Beige needles  Form: Free NMR (16)                           Reference Example 46                                                           R.sup.5 : --(CH.sub.2).sub.2 CH.sub.3 (3-position) m: 1 A: --CH.sub.2                                      -- R.sup.4 : H                                   M.p. 110.0--111.0° C.                                                                   Solvent for recrystallization: Ethyl acetate-n-hexane          Crystalline form: Pale yellow needles                                                               Form: Free                                                  Reference Example 47                                                           R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (3-position) m: 1 A: --CH.sub.2                                      -- R.sup.4 : H                                   M.p. 110.5-111.0° C.                                                                    Solvent for recrystallization: Ethyl acetate-n-hexane          Crystalline form: Pale yellow needles                                                               Form: Free                                                  Reference Example 48                                                            -                                                                                                           m: 1 A: --CH.sub.2 -- R.sup.4 : H                                              -                                              M.p. 93.7-94.0° C.                                                                      Solvent for recrystallization: Ethyl acetate-n-hexane          Crystalline form: Pink powder                                                                       Form: Free                                                __________________________________________________________________________

                  TABLE 9                                                          ______________________________________                                                 Reference Example 49                                                     R.sup.5 : Cl (3-position)                                                      m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Pale yellow powder                                           Form: Free                                                                     NMR (17)                                                                       Reference Example 50                                                           R.sup.5 : F (3-position)                                                       m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Pale yellow powder                                           Form: Free                                                                     NMR (18)                                                                       Reference Example 51                                                           R.sup.5 : CH.sub.3 O (3-position)                                              m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Beige powder                                                 Form: Free                                                                     NMR (19)                                                                       Reference Example 52                                                           R.sup.5 : C.sub.2 H.sub.5 O (3-position)                                       m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Brown powder                                                 Form: Free                                                                     NMR (20)                                                                     ______________________________________                                    

¹ H-NMR spectrum (NMR (1) to NMR (20)) as described in Tables 5 to 9 are as follows:

NMR (1) (DMSO-d₆) δppm: 2.45 (3H, s), 4.95 (2H, s), 6.81-6.95 (2H, m), 7.10-7.22 (2H, m), 7.32 (1H, t, J=6.1 Hz), 7.45 (1H, t, J=6.4 Hz), 7.77 (1H, d), J=6.4 Hz), 7.99 (1H, d, J=6.3 Hz), 12.60 (1H, s); NMR (2) (DMSO-d₆) δppm: 1.18 (3H, t, J=7.5 Hz), 2.67 (2H, q, J=7.5 Hz), 4.96 (2H, s), 6.89 (2H, dd, J=8.0 Hz, J=12.5 Hz), 7.09-7.23 (2H, m), 7.28-7.38 (1H, m), 7.40-7.52 (1H, m), 7.77 (1H, d, J=8.0 Hz), 7.98 (1H, d, J=7.8 Hz), 12.58 (1H, s); NMR (3) (CDCl₃) δppm: 1.03 (3H, t, J=7.4 Hz), 1.6-1.8 (2H, m), 2.73 (2H, t, J=7.4 Hz), 4.76 (2H, s), 6.84 (1H, d, J=8.0 Hz), 7.01-7.50 (5H, m), 7.79-7.86 (2H, m), 9.6-9.8 (1H, s); NMR (4) (CDCl₃) δppm: 0.95 (3H, t J=7.2 Hz), 1.37-1.55 (2H, m), 1.59-1.74 (2H, m), 2.71 (2H, d, J=7.2 Hz), 4.77 (2H, s), 6.82 (1H, d, J=8.1 Hz), 6.98-7.06 (1H, m), 7.16-7.26 (2H, m), 7.30-7.38 (1H, m), 7.41-7.50 (1H, m), 7.79-7.86 (2H, m), 9.78 (1H, brs); NMR (5) (CDCl₃) δppm: 4.76 (2H, s), 6.95-7.11 (3H, m), 7.26-7.47 (4H, m), 7.79-7.87 (2H, m), 9.92 (1H, br); NMR (6) (CDCl₃) δppm: 0.92 (3H, t, J=6.8 Hz), 1.30-1.55 (4H, m), 1.55-1.90 (2H, m), 2.71 (2H, t, J=7.6 Hz), 4.77 (2H, s), 6.82 (1H, d, J=8.0 Hz), 6.98-7.05 (1H, m), 7.17-7.26 (2H, m), 7.31-7.38 (1H, m), 7.42-7.50 (1H, m), 7.79-7.87 (2H, m), 9.73 (1H, brs); NMR (7) (DMSO-d₆) δppm: 5.03 (2H, s), 6.90-7.07 (1H, m), 7.07-7.20 (2H, m), 7.20-7.50 (2H, m), 7.45 (1H, dt, J=1.3 Hz, J=7.3 Hz), 7.77 (1H, d, J=7.8 Hz), 7.99 (1H, dd, J=0.7 Hz, J=7.7 Hz), 12.63 (1H, s); NMR (8) (CDCl₃) δppm: 4.80 (2H, s), 6.95-7.10 (2H, m), 7.23-7.49 (4H, m), 7.85 (2H, dd, J=2.0 Hz, J=6.6 Hz), 9.97 (1H, br); NMR (9) (CDCl₃) δppm: 1.75-2.0 (4H, m), 2.75-2.9 (4H, m), 4.74 (2H, s), 6.63 (1H, d, J=8 Hz), 6.82 (1H, d, J=8 Hz), 7.05-7.15 (1H, m), 7.3-7.5 (2H, m), 7.75-7.9 (2H, m), 9.73 (1H, br); NMR (10) (CDCl₃) δppm: 2.29 (3H, s), 2.32(3H, s), 4.75 (2H, s), 6.70 (1H, d, J=8 Hz), 6.90 (1H, d, J=7.5 Hz), 7.05-7.15 (1H, m), 7.3-7.5 (2H, m), 7.75-7.9 (2H, m), 9.76 (1H, br); NMR (11) (DMSO-d₆) δppm: 2.27 (6H, s), 4.63 (2H, s), 6.90-7.12 (3H, s), 7.29-7.40 (1H, m), 7.42-7.52 (1H, s), 7.76 (1H, d, J=7.8 Hz), 8.02 (1H, d, J=7.4 Hz), 12.49 (1H, s); NMR (12) (CDCl₃) δppm: 2.32 (6H, s), 4.73 (2H, s), 6.61 (2H, s), 6.72 (1H, s), 7.3-7.55 (2H, m), 7.8-7.95 (2H, m), 9.86 (1H, br); NMR (13) (CDCl₃) δppm: 2.18 (2H, tt, J=7.0 Hz, J=8.0 Hz), 2.96 (2H, t, J=7.0 Hz), 3.63 (2H, t, J=8.0 Hz), 4.80 (2H, s), 6.87 (1H, d, J=8.5 Hz), 7.04 (1H, t, J=7.2 Hz), 7.15-7.29 (2H, m), 7.34 (1H, t, J=8.9 Hz), 7.43 (1H, t, J=8.0 Hz), 7.79-7.87 (2H, m), 9.73 (1H, br); NMR (14) (CDCl₃) δppm: 3.22 (2H, t, J=7.0 Hz), 3.82 (2H, t, J=7.0 Hz), 4.81 (2H, s), 6.86 (1H, d, J=8.2 Hz), 7.05 (1H, t, J=7.2 Hz), 7.15-7.52 (4H, m), 7.81 (2H, t, J=8.4 Hz), 9.78 (1H, br); NMR (15) (CDCl₃) δppm: 2.37 (3H, s), 4.74 (2H, s), 6.74-6.85 (2H, m 6.85 (1H, d, J=7.3 Hz), 7.17-7.30 (1H, m), 7.30-7.40 (1H, m), 7.40-7.54 (1H, m), 7.77-7.90 (2H, m), 9.88 (1H, brs); NMR (16) (CDCl₃) δppm: 1.25 (3H, t, J=7.6 Hz), 2.65 (2H, q, J=7.6 Hz), 4.74 (2H, s), 6.74-6.84 (2H, m), 6.88-6.95 (1H, m), 7.21-7.50 (3H, m), 7.79-7.86 (2H, m), 9.94 (1H, br); NMR (17) (CDCl₃) δppm: 4.73 (2H, s), 6.75-6.84 (1H, m), 6.84-6.98 (1H, m), 7.01-7.08 (1H, m), 7.21-7.46 (3H, m), 7.82 (2H, t, J=8.4 Hz), 10.09 (1H, br); NMR (18) (DMSO-d₆) δppm: 4.94 (2H, s), 6.75-6.92 (3H, m), 7.27-7.47 (3H, m), 7.75 (1H, d, J=8.0 Hz), 7.97 (1H, d, J=8.0 Hz); NMR (19) (CDCl₃) δppm: 3.81 (3H, s), 4.73 (2H, s), 6.53-6.65 (3H, m), 7.20-7.51 (3H, m), 7.79-7.86 (2H, m), 9.89 (1H, br); NMR (20) (CDCl₃) δppm: 1.43 (3H, t, J=7.0 Hz), 4.04 (2H, q, J=7.0 Hz), 4.73 (2H, s), 6.50-6.66 (3H, m), 7.18-7.51 (3H, m), 7.78-7.90 (2H, m), 9.87 (1H, br).

Using the suitable starting compounds, the compounds as listed in Table 10 are obtained in the same manner as in Reference Example 3.

                                      TABLE 10                                     __________________________________________________________________________      ##STR154##                                                                    __________________________________________________________________________     Reference Example 53                                                             R.sup.5 : C.sub.2 H.sub.5 O (2-position) m: 1 A: --CH.sub.2 -- R.sup.4                                     : H R.sup.18 : CH.sub.3 O                          Crystalline form: Pale yellow powder  Form: Free  NMR (1)                      Reference Example 54                                                            -                                                                                                           m: 1 A: --CH.sub.2 -- R.sup.4 : H                                            R.sup.18 : CH.sub.3 O                               - Crystalline form: White powder  Form: Free  NMR (2)                         Reference Example 55                                                           R.sup.5 : CF.sub.3 CH.sub.2 O (3-position) m: 1 A: --CH.sub.2 --                                           R.sup.4 : H R.sup.18 : CH.sub.3 O                  Crystalline form: White powder  Form: Free  NMR (3)                            Reference Example 56                                                           R.sup.5 : CF.sub.3 (2-position) m: 1 A: --CH.sub.2 -- R.sup.4 : H                                          R.sup.18 : CH.sub.3 O                              Crystalline form: White powder  Form: Free  NMR (4)                            Reference Example 57                                                           R.sup.5 : CH.sub.3 O (3-position) m: 1 A: --CH.sub.2 -- R.sup.4 : H                                        R.sup.18 : CH.sub.3 O                              Crystalline form: White powder  Form: Free  NMR (5)                          __________________________________________________________________________

¹ H-NMR spectrum (NMR (1) to NMR (5)) as described in Table 10 are as follows:

NMR (1) (CDCl₃) δppm: 1.58 (3H, t, J=7.0 Hz), 3.61 (2H, d, J=22.8 Hz), 3.76 (3H, s), 3.82 (3H, s), 4.25 (2H, q, J=7.0 Hz), 4.85 (2H, s), 7.04 (1H, d, J=8.6 Hz), 7.33 (1H, t, J=7.5 Hz), 7.46 (1H, t, J=7.5 Hz), 7.60-7.65 (2H, m), 7.79-7.86 (2H, m), 10.28 (1H, br); NMR (2) (CDCl₃) δppm: 1.47 (6H, d, J=6.0 Hz), 3.74 (3H, s), 3.79 (3H, s), 3.85 (2H, d, J=20.2 Hz), 4.69 (1H, sept, J=6.0 Hz), 4.79 (2H, s), 6.51-6.56 (2H, m), 7.36 (1H, t, J=7.0 Hz), 7.49 (1H, t, J=7.0 Hz), 7.79-7.88 (3H, m), 9.98 (1H, br; NMR (3) (CDCl₃) δppm: 3.76 (2H, d, J=21.3 Hz), 3.75 (3H, s), 3.80 (3H, s), 4.40 (2H, q, J=7.9 Hz), 4.79 (2H, s), 6.44 (1H, d, J=2.2 Hz), 6.60 (1H, dd, J=2.2 Hz, J=8.8 Hz), 7.34 (1H, dt, J=1.3 Hz, J=7.3 Hz), 7.45 (1H, dt, J=1.3 Hz, J=7.3 Hz), 7.75-7.86 (3H, m); NMR (4) (DMSO-d₆) δppm: 3.62 (3H, s), 3.68 (3H, s), 3.93 (2H, d, J=22.5 Hz), 5.27 (2H, s), 7.3-7.55 (3H, m), 7.78 (1H, d, J=8 Hz), 7.98 (1H, d, J=8 Hz), 8.2-8.35 (2H, m), 12.68 (1H, br); NMR (5) (CDCl₃) δppm: 3.74 (3H, s), 3.80 (3H, s), 3.81 (2H, d, J=21 Hz), 3.95 (3H, s), 4.81 (2H, s), 6.5-6.65 (2H, m), 7.25-7.55 (2H, m), 7.75-7.95 (3H, m), 10.01 (1H, s).

Using the suitable starting compounds, the compounds as listed in Tables 11-13 are obtained in the same manner as in Reference Example 4.

                                      TABLE 11                                     __________________________________________________________________________      ##STR156##                                                                    __________________________________________________________________________     Reference Example 58                                                             R.sup.5 : H m:1 A: --CH.sub.2 -- R.sup.4 : H X: Br                             Crystalline form: Pale yellow powder  Form: Free  NMR (1)                      Reference Example 59                                                           R.sup.5 : CH.sub.3 (2-position) m: 1 A: --CH.sub.2 -- R.sup.4 : H X: Cl        Crystalline form: Beige powder  Form: Free  NMR (2)                            Reference Example 60                                                           R.sup.5 : C.sub.2 H.sub.5 (2-position) m: 1 A: --CH.sub.2 -- R.sup.4 :                                      H X: Cl                                           Crystalline form: Beige powder  Form: Free  NMR (3)                            Reference Example 61                                                           R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (2-position) m: 1 A: --CH.sub.2                                       -- R.sup.4 : H X: Cl                              Crystalline form: White powder  Form: Free  NMR (4)                          __________________________________________________________________________

                  TABLE 12                                                         ______________________________________                                         Reference Example 62                                                             R.sup.5 : Cl (2-position)                                                      m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    X: Cl                                                                          M.p. 199-201° C.                                                        Solvent for recrystallization: 1,2-Dichloroethane-n-hexane                     Crystalline form: White powder                                                 Form: Free                                                                     Reference Example 63                                                           R.sup.5 : --(CH.sub.2).sub.2 Cl (2-position)                                   m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    X: Br                                                                          Crystalline form: Pale yellow powder                                           Form: Free                                                                     NMR (5)                                                                        Reference Example 64                                                           R.sup.5 : --(CH.sub.2).sub.3 Cl (2-position)                                   m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    X: Br                                                                          Crystalline form: Pale yellow powder                                           Form: Free                                                                     NMR (6)                                                                        Reference Example 65                                                           R.sup.5 : --(CH.sub.2).sub.4 Cl (2-position)                                   m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    X: Cl                                                                          M.p. 146.5-149° C.                                                      Solvent for recrystallization: Ethyl acetate-n-hexane                          Crystalline form: White powder                                                 Form: Free                                                                   ______________________________________                                    

                                      TABLE 13                                     __________________________________________________________________________     Reference Example 66                                                             R.sup.5 : --(CH.sub.2).sub.2 CO.sub.2 C.sub.2 H.sub.5 (2-position) m: 1                                           A: --CH.sub.2 -- R.sup.4 : H X: Cl                                              M.p. 131.0-133.0° C.                                                    Solvent for recrystallization:                                                Ethyl acetate-n-hexane                      Crystalline form: White powder Form: Free                                      Reference Example 67                                                           R.sup.5 : --(CH.sub.2).sub.2 CO.sub.2 CH.sub.3 (2-position) m: 1 A:                                               --CH.sub.2 -- R.sup.4 : H X: Cl                                                 Crystalline form: White powder                                                Form: Free NMR (7)                          Reference Example 68                                                            -                                                                                                                  m: 1 A: --CH.sub.2 -- R.sup.4 : H                                            X: Cl                                        - Crystalline form: White powder Form: Free NMR (8)                           Reference Example 69                                                            -                                                                                                                  m: 1 R.sup.4 : H X: Cl                    M.p. 206-208° C.                                                      Solvent for recrystallization: Dimethylformamide-ethanol                       Crystalline form: White powder                                                                       Form: Free                                               __________________________________________________________________________

¹ H-NMR spectrum (NMR (1) to NMR (8)) as described in Tables 11-13 are as follows:

NMR (1) (CDCl₃) δppm: 4.41 (2H, s), 4.84 (2H, s), 7.07 (2H, d, J=9.0 Hz), 7.36 (1H, t, J=7.3 Hz), 7.45 (1H, t, J=7.3 Hz), 7.88 (2H, t, J=8.5 Hz), 8.03 (2H, d, J=9.0 Hz); NMR (2) (DMSO-d₆) δppm: 2.30 (3H, s), 5.11 (4H, s), 7.00-7.10 (1H, m), 7.28-7.40 (1H, m), 7.40-7.55 (1H, m), 7.70-7.93 (3H, m), 7.98 (1H, d, J=7.1 Hz), 12.68 (1H, s); NMR (3) (DMSO-d₆) δppm: 1.21 (3H, t, J=7.4 Hz), 2.72 (2H, q, J=7.4 Hz), 5.12, 5.13 (4H, each s), 7.02 (1H, d, J=8.6 Hz), 7.31 (1H, dt, J=1.2 Hz, J=7.3 Hz), 7.45 (1H, dt, J=1.3 Hz, J=7.3 Hz), 7.75-7.92 (3H, m), 7.95-8.00 (1H, m), 12.68 (1H, brs); NMR (4) (CDCl₃) δppm: 0.97 (3H, t, J=7.2 Hz), 1.39-1.59 (2H, m), 1.59-1.86 (2H, m), 2.77 (2H, t, J=7.6 Hz), 4.67 (2H, s), 4.86 (2H, s), 6.89 (1H, d, J=8.6 Hz), 7.32-7.39 (1H, m), 7.43-7.51 (1H, m), 7.79-7.87 (4H, m), 9.10-10.01 (1H, brs); NMR (5) (CDCl₃) δppm: 3.16 (2H, t, J=6.9 Hz), 3.92 (2H, t, J=6.9 Hz), 4.83 (2H, s), 5.13 (2H, s), 7.07 (1H, d, J=9.4 Hz), 7.31 (1H, t, J=6.9 Hz), 7.45 (1H, t, J=8.3 Hz), 7.76 (1H, d, J=7.9 Hz), 7.82-8.06 (3H, m); NMR (6) (CDCl₃) δppm: 2.17 (2H, tt, J=6.1 Hz, J=7.5 Hz), 3.03 (2H, t, J=7.5 Hz), 3.64 (2H, t, J=6.1 Hz), 4.40 (2H, s), 4.88 (2H, s), 6.95 (1H, d, J=9.3 Hz), 7.35 (1H, t, J=6.8 Hz), 7.47 (1H, t, J=9.4 Hz), 7.80-7.94 (4H, m), 9.68 (1H, br); NMR (7) (CDCl₃) δppm: 2.75 (2H, t, J=7.0 Hz), 3.13 (2H, t, J=7.0 Hz), 3.74 (3H, s), 4.65 (2H, s), 4.89 (2H, s), 6.89 (1H, d, J=8.4 Hz), 7.30-7.37 (1H, m), 7.41-7.48 (1H, m), 7.78-7.89 (4H, m), 9.00-11.30 (1H, brs); NMR (8) (CDCl₃) δppm: 2.00 (3H, s), 2.09 (3H, s), 3.08 (1H, dd, J=8 Hz, J=14 Hz), 3.23 (1H, dd, J=6 Hz, J=14 Hz), 4.14 (1H, dd, J=5.5 Hz, J=12 Hz), 4.33 (1H, dd, J=3 Hz, J=12 Hz), 4.64 (2H, s), 4.5 (2H, s), 5.49 (1H, m), 6.90 (1H, d, J=9 Hz), 7.3-8.0 (6H, m), 8.79 (1H, br).

Using the suitable starting compounds, the compounds as listed in Tables 14-22 are obtained in the same manner as in Reference Example 5 or 6.

                                      TABLE 14                                     __________________________________________________________________________      ##STR159##                                                                    __________________________________________________________________________     Reference Example 70                                                             R.sup.5 : H m: 1 A: --CH.sub.2 -- R.sup.4 : H                                  Crystalline form: Pale yellow amorphous  Form: Free NMR (1)                    Reference Example 71                                                           R.sup.5 : CH.sub.3 (2-position) m: 1 A: --CH.sub.2 -- R.sup.4 : H                                            Crystalline fomi: Pale yellow amorphous                                       Form: Free NMR (2)                                Reference Example 72                                                           R.sup.5 : C.sub.2 H.sub.5 (2-position) m: 1 A: --CH.sub.2 -- R.sup.4 :                                      H                                                 Crystalline form: White powder  Form: Free NMR (3)                             Reference Example 73                                                            -                                                                                                            m: 1 A: --CH.sub.2 -- R.sup.4 : H                                              - Crystalline form: White powder  Form:                                      Free NMR (4)                                    __________________________________________________________________________

                  TABLE 15                                                         ______________________________________                                         Reference Example 74                                                             R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (2-position)                             m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Pale yellow powder                                           Form: Free                                                                     NMR (5)                                                                        Reference Example 75                                                           R.sup.5 : Cl (2-position)                                                      m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: Pale yellow amorphous                                        Form: Free                                                                     NMR (6)                                                                        Reference Example 76                                                           R.sup.5 : F (2-position)                                                       m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: White powder                                                 Form: Free                                                                     NMR (7)                                                                        Reference Example 77                                                           R.sup.5 : --(CH.sub.2).sub.2 Cl (2-position)                                   m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: White powder                                                 Form: Free                                                                     NMR (8)                                                                        Reference Example 78                                                           R.sup.5 : --(CH.sub.2).sub.4 Cl (2-position)                                   m: 1                                                                           A: --CH.sub.2 --                                                               R.sup.4 : H                                                                    Crystalline form: White needles                                                Form: Free                                                                     NMR (9)                                                                      ______________________________________                                    

                                      TABLE 16                                     __________________________________________________________________________     Reference Example 79                                                             R.sup.5 : --(CH.sub.2).sub.2 CO.sub.2 C.sub.2 H.sub.5 (2-position) m: 1                                          A: --CH.sub.2 -- R.sup.4 : H                 Crystalline form: White powder Form: Free NMR (10)                             Reference Example 80                                                            -                                                                                                                 m: 1 A: --CH.sub.2 -- R.sup.4 : H                                              - Crystalline form: White powder                                             Form: Free NMR (11)                          Reference Example 81                                                            -                                                                                                                 m: 1 A: --CH.sub.2 -- R.sup.4 : H                                              - Crystalline form: White powder                                             Form: Free NMR (12)                          Reference Example 82                                                            -                                                                                                                 m: 1 A: --CH.sub.2 -- R.sup.4 : H                                              - Crystalline form: Pale yellow                                              amorphous Form: Free NMR (13)              __________________________________________________________________________

                                      TABLE 17                                     __________________________________________________________________________     Reference Example 83                                                             R.sup.5 : --(CH.sub.2).sub.3 N(C.sub.2 H.sub.5).sub.2 (2-position) m: 1                                             A: --CH.sub.2 -- R.sup.4 : H                                                    Crystalline form: White powder                                                Form: Free NMR (14)                       Reference Example 84                                                            -                                                                                                                    m: 1 A: --CH.sub.2 -- R.sup.4 :                                              H                                          - Crystalline form: White powder Form: Free NMR (15)                          Reference Example 85                                                            -                                                                                                                    m: 1 A: --CH.sub.2 -- R.sup.4 :                                              H                                          - Crystalline form: White powder Form: Free NMR (16)                          Reference Example 86                                                            -                                                                                                                    m: 1 A: --CH.sub.2 -- R.sup.4 :                                              H                                          -                                                                           M.p. 153-155 ° C. Solvent for recrystallization: Ethyl acetate                                    Crystalline form: White powder Form: Free            __________________________________________________________________________

                                      TABLE 18                                     __________________________________________________________________________     Reference Example 87                                                            ##STR167##                 m: 1 A: --CH.sub.2 -- R.sup.4 : H                     - Crystalline form: White amorphous Form: Free NMR (17)                       Reference Example 88                                                            -                                                                                                       ##STR m: 1 A: --CH.sub.2 -- R.sup.4 : H                                               - Crystalline form: White amorphous                                          Form Free NMR (18)                              Reference Example 89                                                            -                                                                                                             ##STR m: 1 A: --CH.sub.2 -- R.sup.4 : H         - Crystalline form: Colorless amorphous Form Free NMR (19)                    Reference Example 90                                                            -                                                                                                                    m: 1 A: --CH.sub.2 -- R.sup.4 :                                              H                                          - Crystalline form: Colorless amorphous Form: Free NMR (20)                 __________________________________________________________________________

                                      TABLE 19                                     __________________________________________________________________________     Reference Example 91                                                            ##STR171##                     m: 1 A: --CH.sub.2 -- R.sup.4 : H                                               - Crystalline form: Yellow amorphous                                         Form: Free NMR (21)                               Reference Example 92                                                            -                                                                                                           ##STR m: 1 A: --CH.sub.2 -- R.sup.4 : H                                               - Crystalline form: Colorless                                                amorphous Form: Free NMR (22)                                                   Reference Example 93                        -                                                                                                                 ##STR m: 1 A: --CH.sub.2 -- R.sup.4                                                 : H                                    - Crystalline form: Yellow amorphous Form: Free NMR (23)                      Reference Example 94                                                            -                                                                                                                        m: 1 A: --CH.sub.2 --                                                        R.sup.4 : H                            - Crystalline form: Yellow amorphous Form: Free NMR (24)                    __________________________________________________________________________

                                      TABLE 20                                     __________________________________________________________________________     Reference Example 95                                                            ##STR175##              m: 1 A: --CH.sub.2 -- R.sup.4 : H                        - Crystalline form: White powder Form: Free NMR (25)                          Reference Example 96                                                            -                                                                                                    ##STR m: 1 A: --CH.sub.2 -- R.sup.4 : H                  - Crystalline form: Pale yellow powder Form: Free NMR (26)                    Reference Example 97                                                            -                                                                                                          ##STR m: 1 A: --CH.sub.2 -- R.sup.4 : H                                               - Crystalline form: White amorphous                                          Form: Free NMR (27)                          Reference Example 98                                                            -                                                                                                                 m: 1 A: --CH.sub.2 -- R.sup.4 : H                                              - Crystalline form: White amorphous                                          Form: Free NMR (28)                        __________________________________________________________________________

                                      TABLE 21                                     __________________________________________________________________________     Reference Example 99                                                            ##STR179##                     m: 1 A: --CH.sub.2 -- R.sup.4 : H                                               - Crystalline form: White amorphous                                          Form: Free NMR (29)                               Reference Example 100                                                           -                                                                                                           ##STR m: 1 A: --CH.sub.2 -- R.sup.4 : H                                               - Crystalline form: White amorphous                                           Form Free NMR (30)                         Reference Example 101                                                           -                                                                                                                 ##STR m: 1 A: --CH.sub.2 -- R.sup.4                                                 : H                                    - Crystalline form: Yellow amorphous Form: Free NMR (31)                      Reference Example 102                                                          R.sup.5 : --COOCH.sub.3 (2-position) m: 1 A: --CH.sub.2 -- R.sup.4 : H                                                   Crystalline form: Pale yellow                                                 amorphous Form: Free NMR            __________________________________________________________________________                                                (32)                           

                                      TABLE 22                                     __________________________________________________________________________     Reference Example 103                                                            R.sup.5 : --(CH.sub.2).sub.2 CONH-- (combined at 2- and 3-positions) m:                                          2 A: --CH.sub.2 -- R.sup.4 : H                                                  Crystalline form: Yellow amorphous                                            Form: Free NMR (33)                          Reference Example 104                                                           -                                                                                                                 m: 1 R.sup.4 : H                           Crystalline form: White powder Form: Free NMR (35)                           __________________________________________________________________________

¹ H-NMR spectrum (NMR (1) to NMR (35)) as described in Tables 14-22 are as follows:

NMR (1) (CDCl₃) δppm: 4.37 (1H, d, J=24 Hz), 4.77 (2H, s), 6.91 (2H, d, J=8.8 Hz), 7.16 (1H, t, J=7.3 Hz), 7.32 (1H, t, J=7.3 Hz), 7.38-7.82 (17H, m), 7.89 (2H, d, J=8.8 Hz); NMR (2) (CDCl₃) δppm: 2.35 (3H, s), 4.41 (1H, brs), 4.70 (2H, s), 6.70 (1H, d, J=8.2 Hz), 7.20-8.00 (21H, m); NMR (3) (DMSO-d₆) δppm: 1.19 (3H, t, J=7.4 Hz), 2.69 (2H, q, J=7.4 Hz), 4.43 (1H, d, J=2.5 Hz), 5.00 (2H, s), 6.83 (1H, d, J=8.9 Hz), 7.25-7.38 (1H, m), 7.38-7.85 (19H, m), 7.98 (1H, d, J=7.1 Hz), 12.65 (1H, brs); NMR (4) (CDCl₃) δppm: 1.32 (6H, d, J=7 Hz), 3.42 (1H, sept, J=7 Hz), 4.2-4.6 (1H, m), 4.73 (2H, s), 7.25-8.0 (21H, m), 10.01 (1H, br); NMR (5) (CDCl₃) δppm: 0.86 (3H, t, J=7.2 Hz), 1.31-1.51 (2H, m), 1.51-1.72 (2H, m), 2.65-2.72 (2H, m), 3.76 (3H, s), 4.34 (1H, br-d, J=24.7 Hz), 4.66 (2H, s), 5.98 (1H, br-s), 6.66 (1H, d, J=8.3 Hz), 6.99-7.10 (1H, m), 7.19-7.31 (1H, m), 7.38-7.60 (11H, m), 7.60-7.87 (8H, m); NMR (6) (DMSO-d₆) δppm: 4.52 (1H, d, J=23 Hz), 5.12 (2H, s), 7.07 (1H, d, J=8.4 Hz), 7.31 (1H, td, J=7.6 Hz, J=1.0 Hz), 7.45 (1H, td, J=7.6 Hz, J=1.4 Hz), 7.45-8.15 (19H, m), 12.68 (1H, s); NMR (7) (CDCl₃) δppm: 4.34 (1H, d, J=22 Hz), 4.79 (2H, s), 6.97 (1H, t, J=8.4 Hz), 7.30-7.38 (2H, m), 7.38-7.92 (19H, m), 9.97 (1H, br); NMR (8) (DMSO-d₆) δppm: 3.16 (2H, t, J=7.0 Hz), 3.92 (2H, t, J=7.0 Hz), 4.83 (2H, s), 5.13 (2H, s), 7.07 (1H, d, J=9.4 Hz), 7.34 (1H, t, J=6.5 Hz), 7.44 (1H, t, J=6.5 Hz), 7.60-8.12 (19H, m), 12.70 (1H, br); NMR (9) (CDCl₃) δppm: 1.67-1.90 (4H, m), 2.64-2.82 (2H, m), 3.68 (1H, bt, J=6.0 Hz), 5.19 (2H, s), 6.12 (2H, d, J=14.0 Hz), 7.10 (1H, d, J=10.0 Hz), 7.29-7.41 (1H, m), 7.41-7.52 (1H, m), 7.69-7.95 (17H, m), 7.95-8.06 (2H, m), 12.74 (1H, br-s); NMR (10) (DMSO-d₆) δppm: 1.10 (3H, t, J=7.1 Hz), 2.62 (2H, t, J=8.0 Hz), 2.90 (2H, t, J=8.0 Hz), 4.00 (2H, q, J=7.1 Hz), 4.33 (1H, d, J=30.0 Hz), 5.01 (2H, s), 6.82 (1H, d, J=14.0 Hz), 7.29-7.38 (1H, m), 7.40-7.50 (1H, m), 7.50-7.80 (18H, m), 8.00-8.02 (1H, d, J=4.0 Hz), 12.61 (1H, brs); NMR (11) (CDCl₃) δppm: 2.00 (3H, s), 2.05 (3H,s), 3.0-3.15 (2H, m), 4.0-4.35 (2H, m), 4.93, 5.05 (2H, ABq, J=16 Hz), 5.40 (1H, m), 6.1-6.6 (2H, br), 6.98 (1H, d, J=8 Hz), 7.2-8.5 (2H, m); NMR (12) (CDCl₃) δppm: 2.54-2.78 (6H, m), 2.87-3.12 (2H, m), 3.69-3.90 (4H, m), 4.36 (1H, d, J=24.0 Hz), 4.78 (2H, s), 6.77 (1H, d, J=8.5 Hz), 7.27-7.88 (21H, m); NMR (13) (CDCl₃) δppm: 2.27 (3H, s), 2.32-2.76 (10H, m), 2.76-3.05 (2H, m), 4.36 (1H, d, J=26.0 Hz), 4.71 (2H, s), 6.77 (1H, d, J=8.3 Hz), 7.27-8.02 (21H, m); NMR (14) (CDCl₃) δppm: 1.00 (6H, t, J=7.1 Hz), 1.80-2.00 (2H, m), 2.48-2.62 (6H, m), 2.78 (2H, t, J=6.2 Hz), 4.37 (1H, d, J=24.4 Hz), 4.76 (2H, s), 6.80 (1H, d, J=6.8 Hz), 7.32 (1H, t, J=7.3 Hz), 7.39-7.93 (20H, m); NMR (15) (CDCl₃) δppm: 1.72-2.05 (2H, m), 2.30-2.57 (4H, m), 2.70-2.89 (2H, m), 3.54-3.83 (4H, m), 4.37 (1H, d, J=28.0Hz), 4.74 (2H, s), 6.77 (1H, d, J=8.3 Hz), 7.33 (1H, t, J=7.3 Hz), 7.40-7.96 (20H, m); NMR (16) (CDCl₃) δppm: 1.81-2.01 (2H, m), 2.22 (3H, s), 2.28-2.68 (10H, m), 2.79 (2H, t, J=6.9 Hz), 4.37 (1H, d, J=24.0 Hz), 4.76 (2H, s), 6.79 (1H, d, J=8.4 Hz), 7.33 (1H, t, J=8.8 Hz), 7.40-7.64 (10H, m), 7.64-7.95 (10H, m); NMR (17) (CDCl₃) δppm: 1.7-3.3 (16H, m), 3.59 (2H, m), 4.81 (2H, s), 6.82 (1H, d, J=8.5 Hz), 7.2-8.0 (21H, m); NMR (18) (CDCl₃) δppm: 1.4-1.7 (2H, m), 1.75-2.0 (4H, m), 2.2-2.4 (2H, m), 2.4-2.6 (2H, m), 2.65-2.9 (4H, m), 3.65 (1H, m), 4.1-4.8 (2H, br), 4.68 (2H, s), 6.70 (1H, d, J=8.5 Hz), 7.2-7.9 (21H, m); NMR (19) (CDCl₃) δppm: 1.41-2.31 (9H, m), 2.24 (6H, s), 2.46 (2H, t, J=7.5 Hz), 2.77 (2H, t, J=7.5 Hz), 2.93-3.12 (2H, m), 4.23-4.60 (1H, br), 4.73 (2H, s), 6.75 (1H, d, J=8.5 Hz), 7.23-7.92 (21H, m); NMR (20) (CDCl₃) δppm: 1.48-2.28 (9H, m), 2.36-2.61 (6H, m), 2.77 (2H, t, J=7.5 Hz), 2.92-3.13 (2H, m), 3.65 (4H, t, J=4.5 Hz), 4.19-4.58 (1H, m), 4.70 (2H, s), 6.71 (1H, d, J=8.5 Hz), 7.02-7.94 (21H, m); NMR (21) (CDCl₃) δppm: 1.41-2.03 (8H, m), 2.05-2.80 (13H, m), 2.77 (2H, t, J=7.6 Hz), 2.88-3.07 (2H, m), 4.73 (2H, s), 6.75 (1H, d, J=8.5 Hz), 7.32 (1H, t, J=6.4 Hz), 7.40-7.90 (20H, m); NMR (22) (CDCl₃) δppm: 1.62-2.23 (8H, m), 2.29-2.97 (12H, m), 3.48-3.93 (3H, m), 4.22-4.57 (1H, br), 4.69 (2H, s), 6.70 (1H, d, J=8.5 Hz), 7.22-8.04 (21H, m); NMR (23) (CDCl₃) δppm: 1.69-2.00 (3H, m), 2.00-2.62 (16H, m), 2.62-2.87 (4H, m), 3.50-3.92 (3H, m), 4.37 (1H, d, J=26.8 Hz), 4.75 (2H, s), 6.77 (1H, d, J=8.4 Hz), 7.28-7.92 (21H, m); NMR (24) (CDCl₃) δppm: 1.82-2.22 (4H, m), 2.50 (3H, s), 2.54-3.12 (12H, m), 4.73 (2H, s), 6.71 (1H, d, J=8.6 Hz), 7.29-7.88 (21H, m); NMR (25) (CDCl₃) δppm: 1.55-1.85 (4H, m), 2.3-2.5 (6H, m), 2.7-2.9 (2H, m), 3.67 (4H, t, J=4.5 Hz), 4.25-4.55 (2H, m), 4.76 (2H, s), 6.78 (1H, d, J=8.5 Hz), 7.25-7.95 (21H, m); NMR (26) (DMSO-d₆) δppm: 1.37-1.70 (4H, m), 2.08 (3H, s), 2.14-2.43 (10H, m), 2.60-2.77 (2H, m), 4.33 (1H, d, J=26.0 Hz), 4.96 (2H, s), 6.80 (1H, d, J=10.0 Hz), 7.27-7.38 (1H, m), 7.38-7.80 (19H, m), 7.90-8.03 (1H, m); NMR (27) (CDCl₃) δppm: 1.00 (3H, t, J=7.0 Hz), 1.01 (3H, t, J=7.0 Hz), 2.68 (2H, t, J=6.9 Hz), 3.12-3.27 (4H, m), 3.35-3.46 (2H, m), 4.25-4.60 (1H, m), 4.96 (2H, s), 6.67 (1H, d, J=8.5 Hz), 7.23-7.27 (1H, m), 7.29-7.57 (10H, m), 7.68-7.81 (9H, m), 7.92 (1H, brs), 11.97 (1H, brs); NMR (28) (CDCl₃) δppm: 2.14-2.39 (4H, m), 2.22 (3H, s), 2.74 (2H, t, J=6.3 Hz), 2.98-3.20 (2H, m), 3.29-3.48 (2H, m), 3.63-3.80 (2H, m), 4.17-4.54 (1H, m), 4.73 (2H, s), 6.67 (1H, d, J=8.6 Hz), 7.26-7.33 (1H, m), 7.33-7.62 (10H, m), 7.62-7.85 (9H, m), 7.90 (1H, brs); NMR (29) (CDCl₃) δppm: 0.89 (3H, t, J=7.1 Hz), 1.00 (3H, t, J=7.1 Hz), 2.35-4.47 (15H, m), 4.73 (2H, s), 6.67-6.74 (1H, m), 7.20-7.61 (11H, m), 7.61-7.85 (9H, m), 7.85-7.93 (1H, m); NMR (30) (CDCl₃) δppm: 1.01-1.47 (2H, m), 1.65-1.90 (2H, m), 2.29 (3H, s), 2.35-2.65 (11H, m), 2.65-2.91 (2H, m), 3.03-3.22 (2H, m), 3.73-3.91 (1H, m), 4.22-4.54 (1H, m), 4.73 (2H, s), 4.75-4.92 (1H, m), 6.69 (1H, d, J=8.6 Hz), 7.22-7.63 (11H, m), 7.63-7.88 (9H, m), 7.88-8.00 (1H, m); NMR (31) (CDCl₃) δppm: 2.18-3.50 (20H, m), 3.50-3.71 (1H, m), 3.71-3.95 (1H, m), 4.20-4.82 (4H, m), 6.65-6.74 (1H, m), 7.20-7.63 (12H, m), 7.63-7.86 (9H, m), 7.86-7.98 (1H, m); NMR (32) (CDCl₃) δppm: 4.09 (3H, s), 4.42 (1H, d, J=22.9 Hz), 4.85 (2H, s), 6.93 (1H, d, J=8.7 Hz), 7.00-7.18 (1H, m), 7.18-7.98 (18H, m), 8.19 (1H, dd, J=2.2 Hz, J=8.7 Hz), 8.60 (1H, d, J=2.2 Hz), 11.55 (1H, br); NMR (33) (CDCl₃) δppm: 2.73 (2H, t, J=7.4 Hz), 3.37 (2H, t, J=7.4 Hz), 4.06 (1H, d, J=20.6 Hz), 4.84 (2H, s), 6.77 (1H, d, J=8.6 Hz), 7.28-7.77 (20H, m), 10.85 (1H, br), 12.16 (1H, br); NMR (35) (DMSO-d₆) δppm: 2.03-2.46 (2H, m), 2.67-3.06 (2H, m), 4.28-4.52 (1H, m), 4.94-5.24 (1H, m), 6.83-8.11 (22H, m), 12.61 (1H, brs).

Using the suitable starting compounds, the compounds as listed in Tables, 23-31 are obtained in the same manner as in Reference Example 2.

                  TABLE 23                                                         ______________________________________                                          ##STR183##                                                                    ______________________________________                                         Reference Example 105                                                            R.sup.1 : H R.sup.2 : H R.sup.4 : H                                            R.sup.5 : H m: 1 A: --CH.sub.2 --                                              Crystalline form: White powder Form: Free NMR (1)                            ______________________________________                                    

¹ H-NMR spectrum (NMR (1)) as described in Table 23 are as follows:

NMR (1) (CDCl₃) δppm: 4.81 (2H, s), 7.05 (1H, d, J=3.5 Hz), 7.25-7.35 (2H, m), 7.45-7.65 (2H, m), 7.50 (1H, d, J=3.5 Hz), 10.00 (1H, s), 10.06 (1H, brs).

                  TABLE 24                                                         ______________________________________                                          ##STR184##                                                                    ______________________________________                                         Reference Example 106                                                            R.sup.1 : H R.sup.2 : H R.sup.4 : H                                            R.sup.5 : H m: 1 A: --(CH.sub.2).sub.3 --                                      Crystalline form: Pale yellow particles Form: Free NMR (1)                     Reference Example 107                                                           -                                                                                                           R.sup.5 : H R.sup.4 : H                           -  m: 1 A: --CH.sub.2 --                                                      Crystalline form: Pale yellow particles Form: Free NMR (2)                     Reference Example 108                                                          R.sup.1 : H R.sup.2 : H R.sup.4 : H                                            R.sup.5 : CH.sub.3 (2- and 6-positions) m: 2 A: --CH.sub.2 --                  Crystalline form: Yellow powder Form: Free NMR (3)                           ______________________________________                                    

                                      TABLE 25                                     __________________________________________________________________________     Reference Example 109                                                                      RSTR186##                                                                    .sup.5 : --CH.sub.2 N(C.sub.2 H.sub.5).sub.2 (2-position)                        -                                                                            R.sup.4 : H                                                                               m: 1  A: --CH.sub.2 --                                    Crystalline form: White powder                                                               Form: Free     NMR (4)                                           Reference Example 110                                                           ##STR187##                                                                                    #STR188##                                                         -                                                                                         R.sup.4 : H                                                                             m: 1  A: --CH.sub.2 --                                    Crystalline form: Yellow powder Form: Free  NMR (5)                          Reference Example 111                                                           ##STR189##    R                                                                             .sup.5 : --(CH.sub.2).sub.2 N(C.sub.2 H.sub.5).sub.2                           (2-position)                                                        -                                                                                         R.sup.4 : H                                                                             m: 1  A: --CH.sub.2 --                                    Crystalline form: Brown powder Form: HCl  NMR (6)                            Reference Example 112                                                           ##STR190##                                                                                    #STR191##                                                         -                                                                                         R.sup.4 : H                                                                             m: 1  A: --CH.sub.2 --                                    Crystalline form: White powder Form: 2HCl  NMR (7)                           __________________________________________________________________________

                                      TABLE 26                                     __________________________________________________________________________     Reference Example 113                                                           ##STR192##       R                                                                             .sup.5 : --(CH.sub.2).sub.3 OH (2-position)                      -                                                                                            R.sup.4 : H                                                                             m: 1  A: --CH.sub.2 --                               Crystalline form: White powder                                                                  Form: Free  NMR (8)                                           Reference Example 114                                                           ##STR193##                                                                                       #STR194##                                                      -                                                                                            R.sup.4 : H                                                                             m: 1  A: --CH.sub.2 --                               Crystallline form: Pale yellow powder                                                           Form: Free     NMR (9)                                        Reference Example 115                                                           ##STR195##       R                                                                             .sup.5 : --CH.sub.2 N(C.sub.2 H.sub.5).sub.2 (2-position)        -                                                                                            R.sup.4 : H                                                                             m: 1  A: --(CH.sub.2).sub.5 --                       Crystalline form: Yellow oil                                                                    Form: Free  NMR (10)                                          Reference Example 116                                                           ##STR196##       R                                                                             .sup.5 : --CH.sub.2 N(C.sub.2 H.sub.5).sub.2 (2-position)                      R.sup.4 : H                                                                             m: 1                                                                              A: --(CH.sub.2).sub.3 --                          Crystalline form: Yellow amorphous                                                              Form: Free  NMR (11)                                          __________________________________________________________________________

                                      TABLE 27                                     __________________________________________________________________________     Reference Example 117                                                           ##STR197##                                                                                      #STR198##                                                       -                                                                                           R.sup.4 : H                                                                           m: 1        A: --CH.sub.2 --                            Crystalline form: Pale yellow powder                                                                  Form: Free    NMR (12)                                  Reference Example 118                                                           ##STR199##                                                                                      #STR200##                                                       -                                                                                           R.sup.4 : H                                                                            m: 1       A: --CH.sub.2 --                            Crystalline form: Yellow powder                                                                  Form: 2HCl         NMR (13)                                  Reference Example 119                                                           ##STR201##                                                                                      #STR202##                                                       -                                                                                           R.sup.4 : H                                                                            m: 1       A: --CH.sub.2 --                            Crystalline form: Pale yellow powder                                                                   Form: 2HCl NMR (14)                                    Reference Example 120                                                           ##STR203##      R                                                                             .sup.5 : H R.sup.4 : H                                            -  m: 1 A: --CH.sub.2 --                                                    Crystalline form: Yellow powder                                                                  Form: Free       NMR (15)                                    __________________________________________________________________________

                                      TABLE 28                                     __________________________________________________________________________     Reference Example 121                                                            R.sup.1 : CH.sub.3 R.sup.2 : H R.sup.4 : H                                     R.sup.5 : H m: 1 A: --CH.sub.2 --                                              Crystalline form: Pale brown powder Form: Free NMR (16)                        Reference Example 122                                                          R.sup.1 : (CH.sub.3).sub.3 C-- R.sup.2 : H R.sup.4 : H                         R.sup.5 : H m: 1 A: --CH.sub.2 --                                              Crystalline form: White powder Form: Free NMR (17)                             Reference Example 123                                                           -                                                                                                        R.sup.2 : H R.sup.4 : H                              - R.sup.5 : H m: 1 A: --CH.sub.2 --                                           Crystalline form: Pale yellow powder Form: Free NMR (18)                     Reference Example 124                                                           ##STR205##                                                                                  #STR206##                                                           -                                                                                       R.sup.4 : H                                                                        m: 1     A: --CH.sub.2 --                                      Crystalline form: Pale yellow oil                                                            Form: Free NMR (19)                                              __________________________________________________________________________

                                      TABLE 29                                     __________________________________________________________________________     Reference Example 125                                                                     #STR207##                                                                      #STR208##                                                           R.sup.4 : H                                                                         m: 1                                                                               A: --CH.sub.2 --                                                      Crystalline form: Yellow amorphous                                                               Form: Free                                                                               NMR (20)                                           Reference Example 126                                                                     #STR209##                                                                      #STR210##                                                                    R.sup.4 : H                                                                             m: 1    A: --CH.sub.2 --                                     Crystalline form: Yellow amorphous                                                               Form: Free                                                                               NMR (21)                                           Reference Example 127                                                                     #STR211##                                                                      #STR212##                                                                    R.sup.4 : H                                                                             m: 1    A: --CH.sub.2 --                                     Crystalline form: Yellow amorphous                                                               Form: Free                                                                               NMR (22)                                           Reference Example 128                                                                     #STR213##                                                                      #STR214##                                                                    R.sup.4 : H                                                                             m: 1    A: --CH.sub.2 --                                     Crystalline form: Yellow amorphous                                                               Form: Free                                                                               NMR (23)                                           __________________________________________________________________________

                                      TABLE 30                                     __________________________________________________________________________     Reference Example 129                                                           ##STR215##                                                                                        #STR216##                                                     -                                                                                             R.sup.4 : H                                                                           m: 1      A: --CH.sub.2 --                            Crystalline form: Pale yellow amorphous                                                                 Form: Free  NMR (24)                                  Reference Example 130                                                           ##STR217##                                                                                        #STR218##                                                     -                                                                                             R.sup.4 : H                                                                           m: 1      A: --CH.sub.2 --                            Crystalline form: Pale yellow amorphous                                                                 Form: Free  NMR (25)                                  Reference Example 131                                                           ##STR219##                                                                                        #STR220##                                                     -                                                                                             R.sup.4 : H                                                                           m: 1      A: --CH.sub.2 --                            Crystalline form: Pale yellow amorphous                                                                 Form: Free  NMR (26)                                  Reference Example 132                                                           ##STR221##                                                                                        #STR222##                                                     -                                                                                             R.sup.4 : H                                                                           m: 1      A: --CH.sub.2 --                            Crystalline form: Yellow amorphous                                                                      Form: Free  NMR (27)                                  __________________________________________________________________________

                                      TABLE 31                                     __________________________________________________________________________     Reference Example 133                                                           ##STR223##                                                                                       #STR224##                                                      -                                                                                            R.sup.4 : H                                                                           m: 1     A: --CH.sub.2 --                              Crystalline form: Yellow amorphous                                                                     Form: Free NMR(28)                                     Reference Example 134                                                           ##STR225##                                                                                       #STR226##                                                      -                                                                                            R.sup.4 : H                                                                           m: 1     A: --CH.sub.2 --                              Crystalline form: Colorless amorphous                                                                  Form: Free NMR (29)                                    Reference Example 135                                                           ##STR227##                                                                                       #STR228##                                                      -                                                                                            R.sup.4 : H                                                                           m: 1                                                   Crystalline form: White oil                                                                         Form: Free  NMR (30)                                      __________________________________________________________________________

¹ H-NMR spectrum (NMR (1) to NMR (30)) as described in Tables 24-31 are as follows:

NMR (1) (DMSO-d₆) δppm: 2.08 (2H, q, J=6.6 Hz), 2.62 (2H, t, J=7.2 Hz), 4.13 (2H, t, J=4.1 Hz), 7.10 (2H, d, J=8.6 Hz), 7.19 (1H, d, J=3.6 Hz), 7.45 (1H, d, J=3.6 Hz), 7.85 (2H, d, J=8.6 Hz), 9.86 (1H, s), 12.13 (1H, s); NMR (2) (DMSO-d₆) δppm: 5.07 (2H, s), 7.19 (2H, d, J=8.7 Hz), 7.27-7.40 (1H, m), 7.40-7.56 (1H, m), 7.77 (1H, d, J=7.5 Hz), 7.90 (2H, d, J=8.8 Hz), 7.98 (1H, d, J=7.1 Hz), 9.89 (1H, s), 12.1-13.0 (1H, br); NMR (3) (CDCl₃) δppm: 2.38 (6H, s), 4.57 (2H, s), 7.06 (1H, d, J=3.6 Hz), 7.51 (1H, d, J=3.6 Hz), 7.61 (2H, s), 9.92 (1H, s), 10.10 (1H, brs); NMR (4) (CDCl₃) δppm: 1.13 (6H, t, J=7.1 Hz), 2.93 (4H, q, J=7.1 Hz), 3.79 (2H, s), 5.01 (2H, s), 7.08 (1H, d, J=8.2 Hz), 7.23-7.35 (1H, m), 7.35-7.45 (1H, m), 7.74-7.87 (4H, m), 9.92 (1H, s), 10.71 (1H, s); NMR (5) (CDCl₃) δppm: 2.33 (3H, s), 2.42-2.88 (8H, m), 3.71 (2H, s), 4.92 (2H, s), 7.02 (1H, d, J=8.2 Hz), 7.27-7.40 (1H, m), 7.40-7.59 (1H, m), 7.67-7.93 (1H, m), 9.93 (1H, s); NMR (6) (CDCl₃) δppm: 1.29 (6H, t, J=7.1 Hz), 2.98-3.48 (8H, m), 5.20 (2H, s), 7.22 (1H, d, J=9.0 Hz), 7.35 (1H, d, J=7.6 Hz), 7.49 (1H, d, J=7.6 Hz), 7.80 (1H, d, J=7.8 Hz), 7.85-7.98 (2H, m), 8.01 (1H, d, J=7.4 Hz), 9.91 (1H, s), 10.36 (1H, br), 12.84 (1H, br); NMR (7) (CDCl₃) δppm: 2.86 (3H, s), 3.14-4.00 (12H, m), 5.21 (2H, s), 7.22 (1H, d, J=7.8 Hz), 7.35 (1H, t, J=7.6 Hz), 7.49 (1H, t, J=7.6 Hz), 7.78-7.87 (3H, m), 8.01 (1H, d, J=8.1 Hz), 9.90 (1H, s), 11.60 (2H, br), 12.75 (1H, br); NMR (8) (CDCl₃) δppm: 1.83-2.11 (2H, m), 3.06 (2H, t, J=7.3 Hz), 3.85 (2H, t, J=5.2 Hz), 4.22 (1H, br), 4.85 (2H, s), 6.98 (1H, d, J=8.2 Hz), 7.28-7.41 (1H, m), 7.41-7.49 (1H, m), 7.74-7.86 (4H, m), 9.92 (1H, s), 11.84 (1H, br); NMR (9) (CDCl₃) δppm: 1.83-2.06 (2H, m), 2.25 (3H, s), 2.32-2.76 (10H, m), 2.88 (2H, t, J=7.7 Hz), 4.87 (2H, s), 6.97 (1H, d, J=8.3 Hz), 7.30-7.42 (1H, m), 7.42-7.51 (1H, m), 7.72-7.87 (4H, m), 9.94 (1H, s); NMR (10) (CDCl₃) δppm: 0.99 (6H, t, J=7.1 Hz), 1.40-1.61 (2H, m), 1.70-1.92 (4H, m), 2.43-2.63 (6H, m), 3.56 (2H, s), 3.95 (2H, t, J=6.3 Hz), 6.86 (1H, d, J=8.5 Hz), 7.28-7.40 (1H, m), 7.40-7.51 (1H, m), 7.70-7.91 (3H, m), 7.95 (1H, d, J=2.1 Hz), 9.89 (1H, s). 10.39-13.00 (1H, brs); NMR (11) (CDCl₃) δppm: 0.97 (6H, t, J=7.1 Hz), 2.10-2.40 (2H, m), 2.40-2.68 (6H, m), 3.54 (2H, s), 3.95-4.23 (2H, m), 6.84 (1H, t, J=8.5 Hz), 7.20-7.40 (2H, m), 7.58-7.88 (3H, m), 7.90 (1H, d, J=2.1 Hz), 9.87 (1H, s); NMR (12) (CDCl₃) δppm: 1.38-1.76 (2H, m), 1.76-2.13 (6H, m), 2.13-2.70 (14H, m), 2.88 (2H, t, J=7.6 Hz), 2.95-3.18 (2H, m), 4.86 (2H, s), 6.97 (1H, d, J=8.2 Hz), 7.31-7.42 (1H, m), 7.42-7.57 (1H, m), 7.73-7.87 (4H, m), 9.91 (1H, s); NMR (13) DMSO-d₆) δppm: 1.92-2.45 (6H, m), 2.60-3.21 (9H, m), 3.21-3.76 (4H, m), 3.76-4.16 (4H, m), 5.17 (2H, s), 7.15 (1H, d, J=8.8 Hz), 7.31 (1H, t, J=6.9 Hz), 7.45 (1H, t, J=6.9 Hz), 7.68-7.92 (3H, m), 7.99 (1H, d, J=7.0 Hz), 9.87 (1H, s), 10.73 (1H, br), 11.78 (1H, br), 12.80 (1H, s); NMR (14) (DMSO-d₆) δppm: 1.28 (6H, t, J=7.1 Hz), 2.00-2.38 (6H, m), 2.68-2.90 (2H, m), 2.90-3.25 (8H, m), 3.47-3.83 (3H, m), 5.18 (2H, s), 7.18 (1H, d, J=8.7 Hz), 7.34 (1H, t, J=7.7 Hz), 7.45 (1H, t, J=7.7 Hz), 7.78-7.86 (3H, m), 8.00 (1H, d, J=7.0 Hz), 9.90 (1H, s), 10.78 (2H, br), 12.80 (1H, br); NMR (15) (DMSO-d₆) δppm: 2.40 (3H, s), 5.06 (2H, s), 7.15-7.40 (3H, m), 7.65 (1H, d, J=8.4 Hz), 7.77 (1H, s), 7.89 (2H, d, J=8.6 Hz), 9.88 (1H, s), 12.61 (1H, s); NMR (16) (DMSO-₆) δppm: 2.27 (3H, d, J=0.9 Hz), 4.98 (2H, s), 6.79 (1H, d, J=1.0 Hz), 7.12-7.25 (2H, m), 7.82-7.96 (2H, m), 9.88 (1H, s), 12.0-12.7 (1H, br); NMR (17) (DMSO-d₆) δppm: 1.26 (9H, s), 4.98 (2H, s), 6.78 (1H, s), 7.15 (2H, d, J=8.8 Hz), 7.90 (2H, d, J=8.8 Hz), 9.88 (1H, s), 12.42 (1H, s); NMR (18) (DMSO-d₆) δppm: 5.05 (2H, s), 7.19 (2H, d, J=8.8 Hz), 7.25-7.55 (3H, m), 7.69 (1H, s), 7.80-8.02 (4H, m), 9.89 (1H, s), 12.60 (1H, s); NMR (19) DMSO-d₆) δppm: 1.57-1.84 (7H, m), 1.84-2.05 (3H, m), 2.20 (1H, q, J=8.5 Hz), 2.30-2.72 (8H, m), 2.74-3.12 (3H, m), 3.16-3.30 (1H, m), 4.87 (2H, s), 6.97 (1H, d, J=8.3 Hz), 7.27-7.41 (1H, m), 7.41-7.53 (1H, m), 7.70-7.93 (4H, m), 9.91 (1H, s); NMR (20) (CDCl₃) δppm: 1.67-2.95 (20H, m), 3.55-3.95 (3H, m), 4.90 (2H, s), 6.96 (1H, d, J=8.3 Hz), 7.25-7.53 (2H, m), 7.55-7.95 (4H, m), 9.90 (1H, s); NMR (21) (CDCl₃) δppm: 1.55-3.80 (23H, m), 4.91 (2H, s). 6.96 (1H, d, J=8.4 Hz), 7.25-7.52 (2H, m), 7.65-7.78 (4H, m), 9.88 (1H, s); NMR (22) (CDCl₃) δppm: 1.75-2.95 (16H, m), 3.55-3.95 (7H, m), 4.88 (2H, s), 6.95 (1H, d, J=8.3 Hz) 7.28-7.55 (2H, m), 7.65-7.95 (4H, m), 9.90 (1H, s); NMR (23) (CDCl₃) δppm: 1.75-3.00 (20H, m), 2.27 (3H, s), 3.58-3.98 (3H, m), 4.88 (2H, s), 6.95 (1H, d, J=8.3 Hz), 7.30-7.52 (2H, m), 7.65-7.90 (4H, m), 9.89(1H, s); NMR (24) (CDCl₃) δppm: 1.5-3.4 (15H, m),2.40 (4H, t, J=4.5 Hz), 3.61 (4H, t, J=4.5 Hz), 4.88 (2H, s), 6.99 (1H, d, J=8.5 Hz), 7.3-7.55 (2H, m), 7.7-7.9 (4H, m), 9.92 (1H, s); NMR (25) (CDCl₃) δppm: 1.5-3.1 (23H, m), 2.24 (3H, s), 4.91 (2H, s), 7.00 (1H, d, J=8 Hz), 7.3-7.5 (2H, m), 7.7-7.9 (4H, m), 9.91 (1H, s); NMR (26) (CDCl₃) δppm: 1.7-2.0 (4H, m), 2.33 (3H, s), 2.5-3.0 (12H, m), 4.87 (2H, s), 6.97 (1H, d, J=8 Hz), 7.3-7.9 (6H, m), 9.91 (1H, s); NMR (27) (DMSO-d₆) δppm: 1.30-3.51 (25H, m), 3.51-3.75 (2H, m), 5.16 (2H, s), 7.09 (1H, d, J=8.9 Hz), 7.27-7.39 (1H, m), 7.39-7.52 (1H, m), 7.70-7.84 (3H, m), 7.98-8.09 (1H, m), 9.86 (1H, s), 10.58-11.17 (3H, m); NMR (28) (DMSO-d₆) δppm: 1.45 (6H, s), 2.68-3.01 (2H, m), 2.77 (3H, s), 3.21-3.85 (10H, m), 5.24 (2H, s), 7.10 (1H, d, J=8.3 Hz), 7.29-7.40 (1H, m), 7.40-7.52 (1H, m), 7.74-7.89 (3H, m), 7.93-8.05 (1H, m), 9.89 (1H, s), 11.10-13.00 (3H, m); NMR (29) (CDCl₃) δppm: 1.86 (2H, quint, J=7.5 Hz), 2.18-2.63 (10H, m), 2.30 (3H, s), 3.05 (2H, t, J=7.5 Hz), 4.82 (2H, s), 6.24-7.01 (2H, m), 7.10-7.59 (3H, m), 7.73-7.93 (3H, m), 10.17 (1H, s); NMR (30) (CDCl₃) δppm: 3.46 (1H, dd, J=6.5 Hz, J=16.5 Hz), 3.68 (1H, dd, J=10.5 Hz, J=16.5 Hz), 5.67 (1H, dd, J=6.5 Hz, J=10.5 Hz), 7.08 (1H, d, J=8.5 Hz), 7.25-7.55 (2H, m), 7.75-7.85 (3H, m), 7.99 (2H, d, J=8.5 Hz), 9.84 (1H, s).

Using the suitable starting compounds, the compounds as listed in Tables 32-37 are obtained in the same manner as in Reference Examples 7, 8 or 9.

                  TABLE 32                                                         ______________________________________                                                Reference Example 136                                                            #STR229##                                                                - B.p.: 145° C. (0.3 mmHg)                                             Crystalline form: Colorless oil                                                Form: Free                                                                     NMR (1)                                                                        Reference Example 137                                                           -                                                                                    #STR230##                                                                - Crystalline form: Pale yellow oil                                           Form: Free                                                                     NMR (2)                                                                        Reference Example 138                                                           -                                                                                    #STR231##                                                                - Crystalline form: Colorless oil                                             Form: Free                                                                     NMR (3)                                                                        Reference Example 139                                                           -                                                                                    #STR232##                                                                - Crystalline form: Brown oil                                                 Form: Free                                                                     NMR (4)                                                                        Reference Example 140                                                           -                                                                                    #STR233##                                                                - Crystalline form: Brown oil                                                 Form: Free                                                                     NMR (5)                                                                        Reference Example 141                                                           -                                                                                    #STR234##                                                                - B.p.: 90-95° C. (0.15 mmHg)                                          Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 142                                                           -                                                                                    #STR235##                                                                - B.p.: 90-95° C. (0.2 mmHg)                                           Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 143                                                           -                                                                                    #STR236##                                                                - B.p.: 107° C. (0.35 mmHg)                                            Crystalline form: Colorless oil                                                Form: Free                                                                   ______________________________________                                    

                  TABLE 33                                                         ______________________________________                                         Reference Example 144                                                            #STR237##                                                                       - Crystalline form: White solid                                               Form: Free                                                                     NMR (6)                                                                        Reference Example 145                                                           -                                                                             #STR238##                                                                       - B.p.: 160-154° C. (0.25-0.3 mmHg)                                    Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 146                                                           -                                                                             #STR239##                                                                       - B.p.: 135-140° C. (0.25-0.3 mmHg)                                    Crystalline form: Colorless oil                                                Form: Free                                                                     NMR (7)                                                                        Reference Example 145                                                           -                                                                             #STR240##                                                                       - B.p.: 160-154° C. (0.25-0.3 mmHg)                                    Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 147                                                           -                                                                             #STR241##                                                                       - Crystalline form: Colorless oil                                             Form: Free                                                                     NMR (8)                                                                        Reference Example 148                                                           -                                                                             #STR242##                                                                       - Crystalline form: Colorless oil                                             Form: Free                                                                     NMR (9)                                                                        Reference Example 149                                                           -                                                                             #STR243##                                                                       - Crystalline form: White amorphous                                           Form: Free                                                                     NMR (10)                                                                       Reference Example 150                                                           -                                                                             #STR244##                                                                       - Crystalline form: Colorless oil                                             Form: Free                                                                     NMR (11)                                                                       Reference Example 151                                                           -                                                                             #STR245##                                                                       - Crystalline form: Brown oil                                                 Form: Free                                                                     NMR (12)                                                                     ______________________________________                                    

                  TABLE 34                                                         ______________________________________                                                Reference Example 152                                                            #STR246##                                                                - B.p.: 110-115° C. (0.22 mmHg)                                        Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 153                                                           -                                                                                    #STR247##                                                                - Crystalline form: Pale yellow oil                                           Form: Free                                                                     NMR (13)                                                                       Reference Example 154                                                           -                                                                                    #STR248##                                                                - Crystalline form: Yellow powder                                             Form: Free                                                                     NMR (14)                                                                       Reference Example 155                                                           -                                                                                    #STR249##                                                                - B.p.: 110° C. (0.35 mmHg)                                            Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 156                                                           -                                                                                    #STR250##                                                                - B.p.: 110-115° C. (0.28 mmHg)                                        Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 157                                                           -                                                                                    #STR251##                                                                - B.p.: 120-127° C. (12 mmHg)                                          Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 158                                                           -                                                                                    #STR252##                                                                - B.p.: 113-130° C. (18 mmHg)                                          Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 159                                                           -                                                                                    #STR253##                                                                - B.p.: 165-170° C. (15 mmHg)                                          Crystalline form: Colorless oil                                                Form: Free                                                                     NMR (15)                                                                     ______________________________________                                    

                  TABLE 35                                                         ______________________________________                                         Reference Example 160                                                            #STR254##                                                                       - B.p.: 180-185° C. (15 mmHg)                                          Crystalline form: Colorless oil                                                Free: Form                                                                     NMR (16)                                                                       Reference Example 161                                                           -                                                                             #STR255##                                                                       - B.p.: 138-143° C. (12 mmHg)                                          Crystalline form: Colorless oil                                                Free: Form                                                                     Reference Example 162                                                           -                                                                             #STR256##                                                                       - B.p.: 112-116° C. (0.23 mmHg)                                        M.p. 39-41° C.                                                          Crystalline form: Colorless oil                                                Free: Form                                                                     Reference Example 163                                                           -                                                                             #STR257##                                                                       - B.p.: 116° C. (0.23 mmHg)                                            Crystalline form: Colorless oil                                                Free: Form                                                                     Reference Example 164                                                           -                                                                             #STR258##                                                                       - B.p.: 108° C. (0.3 mmHg)                                             Crystalline form: Colorless oil                                                Free: Form                                                                     Reference Example 165                                                           -                                                                             #STR259##                                                                       - M.p. 73-75.5° C.                                                     Crystalline form: White powder                                                 Free: Form                                                                     Reference Example 166                                                           -                                                                             #STR260##                                                                       - B.p.: 134-137° C. (2.5 mmHg)                                         Crystalline form: Colorless oil                                                Free: Form                                                                     Reference Example 167                                                           -                                                                             #STR261##                                                                       - B.p.: 124-130° C. (0.7 mmHg)                                         Crystalline form: Colorless oil                                                Free: Form                                                                   ______________________________________                                    

                  TABLE 36                                                         ______________________________________                                         Reference Example 168                                                            #STR262##                                                                       - Crystalline form: White powder                                              Form: 3HCl                                                                     NMR (17)                                                                       Reference Example 169                                                           -                                                                             #STR263##                                                                       - Form: Free                                                                  NMR (18)                                                                       Reference Example 170                                                           -                                                                             #STR264##                                                                       - Crystalline form: Colorless oil                                             Form: Free                                                                     NMR (19)                                                                       Reference Example 171                                                           -                                                                             #STR265##                                                                       - Crystalline form: Colorless oil                                             Form: Free                                                                     NMR (20)                                                                       Reference Example 172                                                           -                                                                             #STR266##                                                                       - B.p.: 110-128° C. (20 mmHg)                                          Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 173                                                           -                                                                             #STR267##                                                                       - B.p.: 115-136° C. (20 mmHg)                                          Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 174                                                           -                                                                             #STR268##                                                                       - B.p.: 115-133° C. (20 mmHg)                                          Crystalline form: Colorless oil                                                Form: Free                                                                     Reference Example 175                                                           -                                                                             #STR269##                                                                       - Crystalline form: White powder                                              Form: 3HCl                                                                     NMR (21)                                                                     ______________________________________                                    

                  TABLE 37                                                         ______________________________________                                         Reference Example 176                                                           ##STR270##        B.p.: 165                                                                     -170° C. (18 mmHg)  Crystalline form: Yellow oil                         Form: Free  NMR (22)                                        ______________________________________                                    

¹ H-NMR spectrum (NMR (1) to NMR (22)) as described in Tables 32-37 are as follows:

NMR (1) (CDCl₃) δppm: 1.05 (3H, d, J=6 Hz), 1.25-1.55 (2H, m), 1.75-3.3 (14H, m), 2.31 (3H, s); NMR (2) (CDCl₃) δppm: 0.89 (3H, t, J=7.5 Hz), 1.17-1.54 (3H, m), 1.54-1.78 (1H, m), 1.78-1.94 (2H, m), 1.94-2.18 (3H, m), 2.18-2.49 (6H, m), 2.49-2.72 (2H, m), 2.72-2.95 (3H, m), 3.03-3.27 (2H, m); NMR (3) (CDCl₃) δppm: 0.91 (3H, t, J=7 Hz), 1.15-1.7 (5H, m), 1.75-2.15 (6H, m), 2.28 (3H, s), 2.15-2.45 (3H, m), 2.45-2.65 (2H, m), 2.7-2.95 (3H, m), 3.05-3.25 (2H, m); NMR (4) (CDCl₃) δppm: 0.85-0.94 (6H, m), 1.23-1.54 (2H, m), 1.62 (1H, br), 1.80-1.96 (3H, m), 1.96-2.18 (2H, m), 2.18-2.45 (6H, m), 2.45-2.68 (2H, m), 2.68-2.92 (3H, m), 3.00-3.24 (2H, m); NMR (5) (CDCl₃) δppm: 1.06-1.98 (15H, m), 2.20-2.47 (5H, m), 2.47-2.61 (1H, m), 2.61-2.90 (6H, m), 3.09-3.33 (2H, m); NMR (6) (CDCl₃) δppm: 1.06 (6H, d, J=6.5 Hz), 1.25-1.55 (2H, m), 1.75-1.95 (2H, m), 2.2-2.4 (1H, m), 2.45-2.75 (11H, m), 3.05-3.2 (2H, m); NMR (7) (CDCl₃) δppm: 1.25-1.6 (3H, m), 1.6-2.75 (14H, m), 2.85 (1H, dd, J=2 Hz, J=11.5 Hz), 2.9-3.3 (5H, m); NMR (8) (CDCl₃) δppm: 1.00 (3H, t, J=7.3 Hz), 1.04 (3H, d, J=6.3 Hz), 1.24-1.51 (2H, m), 1.70-1.92 (3H, m), 2.03 (1H, t, J=10.7 Hz), 2.20-2.50 (5H, m), 2.50-2.69 (2H, m), 2.69-3.00 (4H, m), 3.07-3.22 (2H, m); NMR (9) (CDCl₃) δppm: 0.84 (3H, t, J=7.3 Hz), 1.03 (3H, d, J=6.2 Hz), 1.25-1.65 (4H, m), 1.65-1.93 (3H, m), 2.02 (1H, q, J=10.7 Hz), 2.19-2.48 (5H, m), 2.48-2.95 (6H, m), 3.05-3.21 (2H, m); NMR (10) (CDCl₃) δppm: 0.89 (3H, d, J=6.5 Hz), 1.03 (6H, dd, J=6.5 Hz, J=15.1 Hz), 1.44-1.69 (2H, m), 1.80-2.00 (2H, m), 2.05-2.24 (2H, m), 2.24-2.50 (2H, m), 2.50-2.95 (6H, m), 3.13-3.40 (3H, m), 4.85 (1H, br); NMR (11) (CDCl₃) δppm: 1.03 (3H, d, J=6.2 Hz), 1.33-1.52 (2H, m), 1.72-3.08 (16H, m), 3.08-3.23 (2H, m), 3.45-3.80 (2H, m); NMR (12) (CDCl₃) δppm: 1.04 (3H, d, J=6.2 Hz), 1.49-1.68 (2H, m), 1.80-1.99 (2H, m), 2.06 (1H, t, J=10.1 Hz), 2.24-2.55 (5H, m), 2.57-2.88 (4H, m), 2.90-3.10 (2H, m), 3.15-3.31 (3H, m), 3.34 (3H, s), 3.44-3.62 (2H, m); NMR (13) (CDCl₃) δppm: 1.07 (3H, t, J=7.1 Hz), 1.40 (2H, dq, J=3.8 Hz, J=12.0 Hz), 1.65-1.98 (5H, m), 2.39-2.72 (9H, m), 2.72-2.84 (4H, m), 3.05-3.22 (2H, m); NMR (14) (CDCl₃) δppm: 0.91 (3H, t, J=7.1 Hz), 1.14-1.58 (5H, m), 1.58-2.13 (5H, m), 2.22-2.87 (13H, m), 3.01-3.24 (2H, m); NMR (15) (CDCl₃) δppm: 2.0-3.2 (17H, m), 2.26 (3H, s), 2.32 (3H, s); NMR (16) (CDCl₃) δppm: 1.8-1.9 (2H, m), 2.0-3.2 (17H, m), 2.33 (3H, s), 2.34 (3H, s); NMR (17) (DMSO-d₆) δppm: 1.94-2.46 (6H, m), 2.69 (3H, d, J=3.7 Hz), 2.84-3.16 (2H, m), 3.16-4.30 (11H, m), 9.56 (1H, br), 9.99 (1H, br), 11.04 (1H, br), 12.06 (1H, br); NMR (18) (CDCl₃) δppm: 1.08 (3H, d, J=6.2 Hz), 1.28-1.55 (2H, m), 1.55-1.95 (5H, m), 2.38 (3H, s), 2.40-2.99 (10H, m), 3.02-3.22 (2H, m); NMR (19) (CDCl₃) δppm: 1.05 (3H, d, J=6 Hz), 1.25-1.55 (2H, m), 1.75-3.3 (14H, m), 2.31 (3H, s); NMR (20) (CDCl₃) δppm: 1.05 (3H, d, J=6 Hz), 1.25-1.55 (2H, m), 1.75-3.3 (14H, m), 2.31 (3H, s); NMR (21) (DMSO-d₆) δppm: 1.78-2.47 (6H, m), 2.68-3.06 (2H, m), 3.14-4.32 (16H, m), 5.20-5.78 (2H, m), 9.1-9.82 (2H, m), 10.54-11.36 (1H, m), 11.82-12.38 (1H, m); NMR (22) (CDCl₃) δppm: 1.3-1.7 (6H, m), 2.0-3.2 (13H, m), 2.32 (3H, s).

Reference Example 182

To a solution of t-butyl propiolate (9.7 g) in tetrahydrofuran (300 ml) is added dropwise a 1.6M solution of n-butyl lithium in n-hexane (48 ml) at -70° C., and the mixture is reacted for 10 minutes. To the mixture is added dropwise a solution of 2-{(2-methoxy-4-formylphenoxy)methylcarbonylamino}benzothiazole (10 g) in tetrahydrofuran (200 ml) and N,N-dimethylpropylene urea (20 ml) at the same temperature over a period of 20 minutes. The reaction mixture is further reacted for 20 minutes, and then the reaction vessel is taken out from the iced bath, and the mixture is further stirred for 20 minutes. To the mixture is added acetic acid (5 ml), and the mixture is diluted with ethyl acetate. The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, concentrated, and the residue thus obtained is recrystallized from ethyl acetate-n-hexane. The crystals are collected by filtration to give 2-[2-methoxy-4-(3-t-butoxycarbonyl-1-hydroxypropargyl)phenoxymethylcarbonylamino]benzothiazole (13 g) as white power.

Reference Example 183

A solution of sodium hydroxide (4.92 g) in water (5 ml) is diluted with ethanol (80 ml), and the mixture is subjected to deaeration, and then put under nitrogen atmosphere. To the mixture is added 3-methoxy-4-dimethylaminocarbonylthiobenzaldehyde (20 g), and the mixture is refluxed for 14 hours. After cooling, to the mixture is added dropwise ethyl bromoacetate (9.74 ml), and the mixture is stirred at room temperature for three hours. To the mixture are added ethanol, 1.5N hydrochloric acid and water, and the mixture is extracted with chloroform. The extract is dried over sodium sulfate and concentrated, and the residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=9:1→5.6:1→4:1) to give 3-methoxy-4-ethoxycarbonylmethylthiobenzaldehyde (11.8 g) as white solid.

¹ H-NMR (CDCl₃) δppm: 1.21 (3H, t, J=7.1 Hz), 3.74 (2H, s), 3.99 (3H, s), 4.14 (2H, q, J=7.1 Hz), 7.32-7.48 (3H, m), 9.92 (1H, s).

Reference Example 184

Using the suitable starting compounds, the following compound is obtained in the same manner as in Reference Example 1.

α-(2-Methoxy-4-formylphenoxymethyl)acetic acid: Yellow powder; ¹ H-NMR (DMSO-d₆) δppm: 3.84 (3H, s), 4.82 (2H, s), 7.05 (1H, d, J=8 Hz), 7.41 (1H, d, J=2 Hz), 7.51 (1H, dd, J=2 Hz, J=8 Hz), 9.83 (1H, s), 13.14 (1H, br).

Reference Example 185

Using the suitable starting compounds, the following compounds are obtained in the same manner as in Reference Example 2.

2-(2-Methoxy-4-formylphenoxymethylcarbonylamino)benzimidazole: Yellow powder; ¹ H-NMR (CDCl₃) δppm: 4.06 (3H, s), 4.86 (2H, s), 7.09 (1H, d, J=8.5 Hz), 7.3-7.55 (4H, m), 7.8-7.9 (2H, m), 9.91 (1H, s), 10.25 (1H, br).

2-(2-Ethoxy-4-formylphenoxymethylcarbonylamino)benzimidazole: White powder; ¹ H-NMR (CDCl₃) δppm: 1.60 (3H, t, J=7.0 Hz), 4.26 (2H, q, J=7.0 Hz), 4.87 (2H, s), 7.11 (1H, d, J=8.3 Hz), 7.30-7.49 (4H, m), 7.79-7.88 (2H, m), 9.90 (1H, s), 10.34 (1H, br).

2-[2-(Diethylaminocarbonylmethoxy)-4-formylphenoxymethylcarbonylamino]benzimidazole: White powder; ¹ H-NMR (CDCl₃) δppm: 1.16 (3H, t, J=7 Hz), 1.30 (3H, t, J=7 Hz), 3.35 (2H, q, J=7 Hz), 3.49 (2H, q, J=7 Hz), 4.92 (2H, s), 5.00 (2H, s), 7.09 (1H, d, J=8 Hz), 7.25-7.55 (4H, m), 7.7-7.85 (2H, m), 9.86 (1H, s).

Reference Example 186

Using the suitable starting compounds, the following compounds are obtained in the same manner in Reference Example 5.

[3-(2-Chloroethyl)-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyltriphenylphosphonium bromide: ¹ H-NMR (DMSO-d₆) δppm: 3.16 (2H, t, J=7.0 Hz), 3.92 (2H, t, J=7.0 Hz), 5.18 (2H, s), 6.12 (2H, d, J=13.1 Hz), 7.14 (1H, d, J=9.4 Hz), 7.31 (1H, t, J=6.5 Hz), 7.44 (1H, t, J=6.5 Hz), 7.60-8.12 (19H, m), 12.70 (1H, br).

[3-(2,3-Diacetyloxypropyl)-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyltriphenylphosphonium chloride: ¹ H-NMR (CDCl₃) δppm: 2.00 (3H, s), 2.05 (3H, s), 3.0-3.15 (2H, m), 4.0-4.35 (2H, m), 4.93, 5.05 (2H, AB-q, J=16 Hz), 5.40 (1H, m), 6.1-6.6 (2H, br), 6.98 (1H, d, J=8 Hz), 7.2-8.5 (21H, m).

Reference Example 187

To a solution of methyl 2,4-dihydroxybenzoate (25.1 g) in acetone (250 ml) are added methyl bromoacetate (14.9 ml) and potassium carbonate (21.7 g), and the mixture is refluxed for 3 hours. The mixture is filtered, and the filtrate is concentrated, and the residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=3:1) to give ethyl 2-(3-hydroxy-4-methoxycarbonylphenoxy)acetate (31.5 g).

White solid; ¹ H-NMR (CDCl₃) δppm: 3.81 (3H, s), 3.91 (3H, s), 4.65 (2H, s), 6.39 (1H, d, J=2.6 Hz), 6.45 (1H, dd, J=2.6 Hz, J=8.8 Hz), 7.73 (1H, d, J=8.8 Hz), 10.97 (1H, s).

Reference Example 188

To ethanol (50 ml) are added 2-(2-phthalimide)methylbenzothiazole (3.37 g) and hydrazine monohydrate (3 ml), and the mixture is refluxed for 30 minutes. After confirming that the starting compounds are consumed, the precipitated solid is removed by filtration, and the filtrate is concentrated. To the residue is added aqueous potassium carbonate solution, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent to give 2-aminomethylbenzothiazole (1.42 g).

Yellow powder; ¹ H-NMR (CDCl₃) δppm: 1.83 (2H, br), 4.30 (2H, s), 7.33-7.51 (2H, m), 7.85-7.99 (2H, m).

Reference Example 189

To dichloromethane (50 ml) are added 2-hydroxymethylbenzothiazole (2 g) and triethylamine (2.5 ml), and further thereto is added methanesulfonyl chloride (1.03 ml) under ice-cooling, and the mixture is stirred at the same temperature for one hour. After the reaction is complete, the mixture is washed with hydrochloric acid, dried over magnesium sulfate, and concentrated under reduced pressure to the remove the solvent. The resulting crude product is dissolved in dimethylformamide (50 ml), and thereto is added potassium phthalimide (5.6 g). The mixture is heated with stirring at 70° C. for one hour. After the reaction is complete, the reaction mixture is poured into water, and the precipitated crystals are collected by filtration. Separately, the filtrate is extracted with ethyl acetate, and the extract is concentrated under reduced pressure. The residue and the crystals obtained before are combined, and washed with n-hexane-diethyl ether to give 2-(2-phthalimide)methylbenzothiazole (3.37 g).

Yellow powder; ¹ H-NMR (CDCl₃) δppm: 5.30 (2H, s), 7.35-7.47 (2H, m), 7.74-8.02 (6H, m).

Reference Example 190

A solution of methyl p-formylbenzoate (12.33 g), malonic acid (16 g) and piperidine (1 ml) in pyridine (100 ml) is refluxed for two hours. The reaction mixture is poured into ice-water, and the precipitated white powder is collected by filtration, and washed with water, and dried to give 4-methoxycarbonyl cinnamic acid (14.7 g).

White powder; ¹ H-NMR (DMSO-d₆) δppm: 3.85 (3H, s), 6.65 (1H, d, J=16 Hz), 7.63 (1H, d, J=16 Hz), 7.82 (2H, d, J=8 Hz), 8.01 (2H, d, J=8 Hz), 12.57 (1H, br).

Reference Example 191

To a solution of 4-methoxycarbonylcinnamic acid (4.64 g) in acetic acid (300 ml) is added 10% palladium-carbon (0.5 g), and the mixture is subjected to hydrogenation at 70° C. under atmospheric pressure for two hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue is added water, and the precipitated white powder is collected by filtration to give 3-(4-methoxycarbonylphenyl)propionic acid (3.87 g).

White powder; ¹ H-NMR (CDCl₃) δppm: 2.71 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.5 Hz), 3.91 (3H, s), 7.29 (2H, d, J=8.5 Hz), 7.97 (2H, d, J=8.5 Hz).

Reference Example 192

To a suspension of 2-carboxybenzothiazole (6.5 g) in anhydrous dichloromethane (100 ml) are added oxalyl chloride (3.2 ml) and a drop of dimethylformamide, and the mixture is stirred at room temperature for three hours. The mixture is evaporated to remove the dichloromethane, and the residue is dissolved in acetone (100 ml), and added dropwise into an aqueous solution of sodium azide (5 g) in water (20 ml) under ice-cooling. The mixture is stirred at the same temperature for three hours, and thereto is added water. The precipitated crystals are collected by filtration, dissolved in dichloromethane (50 ml), dried, and concentrated under reduced pressure to remove the solvent. To the residue is added benzene (50 ml), and the mixture is refluxed for four hours. To the mixture is added ethyl 4-piperidinecarboxylate (5.7 g), and the mixture is refluxed for 6 hours. To the reaction solution is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=200:1→100:1) to give 2-(4-ethoxycarbonyl-1-piperidinyl)carbonylaminobenzothiazole (4.0 g).

White powder; ¹ H-NMR (CDCl₃) δppm: 1.25 (3H, t, J=7 Hz), 1.65-2.05 (4H, m), 2.4-2.6 (1H, m), 2.95-3.2 (2H, m), 4.0-4.2 (2H, m), 4.14 (2H, q, J=7 Hz), 7.15-7.45 (2H, m), 7.58 (1H, d, J=8 Hz), 7.75 (1H, d, J=8 Hz), 10.11 (1H, br).

Reference Example 193

To a solution of methyl 2-methoxy-4-trifluoromethanesulfonyloxybenzoate (26.8 g), t-butyl acrylate (62.5 ml), triethylamine (25 ml) in anhydrous dimethylformamide (100 ml) are added palladium acetate (0.4 g) and 1,3-bis(diphenylphosphino)propane (0.74 g) under argon atmosphere, and the mixture is heated with stirring at 75° C. for 16 hours. The reaction solution is concentrated under reduced pressure to remove the solvent, and thereto is added water. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:5) to give t-butyl 3-methoxy-4-methoxycarbonylcinnamate (23.5 g).

Yellow powder; ¹ H-NMR (CDCl₃) δppm: 1.54 (9H, s), 3.90 (3H, s), 3.94 (3H, s), 6.42 (1H, d, J=16 Hz), 7.07 (1H, d, J=1.5 Hz), 7.13 (1H, dd, J=1.5, 8 Hz), 7.55 (1H, d, J=16 Hz), 7.80 (1H, d, J=8 Hz).

Reference Example 194

To a solution of t-butyl 3-methoxy-4-methoxycarbonylcinnamate (23.5 g) in anhydrous dichloromethane (100 ml) is added trifluoroacetic acid (50 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure to remove the solvent, and the residue is crystallized from ethanol to give 3-methoxy-4-methoxycarbonylcinnamic acid (8.35 g).

White powder; ¹ H-NMR (CDCl₃ +DMSO-d₆) δppm: 3.88 (3H, s), 3.94 (3H, s), 6.50 (1H, d, J=16 Hz), 7.13 (1H, s), 7.15 (1H, d, J=8 Hz), 7.62 (1H, d, J=16 Hz), 7.78 (1H, d, J=8 Hz).

Reference Example 195

To a suspension of 3-methoxy-4-methoxycarbonylcinnamic acid (8.35 g) in acetic acid (200 ml) is added 10% palladium-carbon (1.0 g), and the mixture is subjected to hydrogenation at room temperature. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is crystallized from diethyl ether-n-hexane to give 3-(3-methoxy-4-methoxycarbonylphenyl)propionic acid (7.5 g).

White powder; ¹ H-NMR (CDCl₃) δppm: 2.70 (2H, t, J=7.5 Hz), 2.98 (2H, t, J=7.5 Hz), 3.88 (3H, s), 3.89 (3H, s), 5.71 (1H, br), 6.75-6.9 (2H, m), 7.75 (1H, d, J=8 Hz).

Reference Example 196

To a solution of dimethyl methylphosphonate (7.7 ml) in anhydrous tetrahydrofuran (100 ml) is added dropwise a 1.66M solution of n-butyl lithium in n-hexane (43 ml) at -50° C. to -60° C. Subsequently, a solution of 2-[2-(3-methoxy-4-methoxycarbonylphenyl)ethyl]carbonylaminobenzothiazole (8.72 g) in anhydrous tetrahydrofuran (50 ml) is added dropwise to the reaction solution. A yellow gummy material generates in the reaction mixture, and thereto is further added 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (10 ml), and the mixture is stirred at the same temperature for two hours. To the reaction mixture is added a saturated aqueous ammonium chloride solution, and the mixture is acidified with diluted hydrochloric acid. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=100:1→10:1) to give dimethyl [{3-methoxy-4-[2-(2-benzothiazolyl)aminocarbonyl)ethyl]benzoyl}methyl]phosphonate (6.4 g), whereby the starting compound (3.1 g) is also recovered.

Yellow powder; ¹ H-NMR (CDCl₃) δppm: 2.80 (2H, t, J=7.5 Hz), 3.05 (2H, t, J=7.5 Hz), 3.73 (3H, s), 3.78 (3H, s), 3.79 (3H, s), 3.82 (2H, d, J=21.5 Hz), 6.65-6.8 (2H, m), 7.25-7.45 (2H, m), 7.60 (1H, d, J=8.5 Hz), 7.64 (1H, d, J=7.5 Hz), 7.82 (1H, dd, J=1 Hz, J=7.5 Hz), 11.49 (1H, br).

Reference Example 197

Dimethyl methylphosphonate (3.9 ml), 1.65M n-butyl lithium (22 ml) and 2-(4-ethoxycarbonyl-1-piperidinyl)carbonylaminobenzothiazole (4.0 g) are treated in the same manner as in Reference Example 196 to give dimethyl [1-(2-benzothiazolyl)aminocarbonyl)-4-piperidinylcarbonylmethyl]phosphonate (2.5 g).

Pale yellow oil; ¹ H-NMR (CDCl₃) δppm: 1.5-2.05 (4H, m), 2.75-3.1 (3H, m), 3.16 (2H, d, J=28 Hz), 3.76 (3H, s), 3.82 (3H, s), 4.1-4.35 (2H, m), 7.15-7.45 (2H, m), 7.57 (1H, d, J=7.5 Hz), 7.74 (1H, d, J=8 Hz), 10.04 (1H, br).

Using the suitable starting compounds, the compounds as listed in Table 36-1 are obtained in the same manner as in Reference Example 1.

                                      TABLE 36-1                                   __________________________________________________________________________       #STR271##                                                                       -                                                                           Ref.                                                                               R.sup.5 (substitution                                                                          M.p. (° C.)                                                                    Crystalline form (Solvent                             Ex. No. position) m A or NMR (Salt) for recrystallization)                   __________________________________________________________________________     198 --(CH.sub.2).sub.3 CH.sub.3 (2)                                                        2 --CH.sub.2 --                                                                        NMR (11)                                                                              White powder                                           --OCH.sub.3 (5)   (Free)                                                      199 --CH.sub.2 CH.sub.3 (2) 2 --CH.sub.2 -- 111.8-112.5 White powder                                    (Ethyl                                                 --OCH.sub.3 (5)   (Free) acetate)                                             200 --CH.sub.3 (2) 2 --CH.sub.2 -- NMR (17) Yellow powder                       --OCH.sub.3 (3)   (Free)                                                      201 --(CH.sub.2).sub.3 CH.sub.3 (2) 2 --CH.sub.2 -- NMR (18) White                                      powder                                                 --OCH.sub.3 (3)   (Free)                                                       - 202 --OCH.sub.3 (3) 1                                                                                  93-95  (Free) White powder  (Diethyl                                         ether-n-hexane)                                        - 203                                                                                                    2 --CH.sub.2 -- 152-154  (Free) Colorless                                    needles                                                - 204                                                                                                    2 --CH.sub.2 -- 122-123  (Free) White powder         - 205 --(CH.sub.2).sub.2 CH.sub.3 (2) 2 --CH.sub.2 -- 95-98 White                                      powder                                                 --OCH.sub.3 (5)   (Free)                                                      206 --CH(CH.sub.3).sub.2 (2) 2 --CH.sub.2 -- NMR (50) White powder                                        --OCH.sub.3 (5)   (Free)                            207 --(CH.sub.2).sub.5 CH.sub.3 (2) 2 --CH.sub.2 -- NMR (51) White                                      powder                                                 --OCH.sub.3 (5)   (Free)                                                      208 --CH.sub.3 (2) 2 --CH.sub.2 -- NMR (55) White powder                        --OCH.sub.3 (5)   (Free)                                                      209 --OCH.sub.3 (2, 5) 2 --CH.sub.2 -- NMR (60) White powder                       (Free)                                                                     210 --OC.sub.2 CH.sub.5 (2) 2 --CH.sub.2 -- NMR (62) White powder                                         --OCH.sub.3 (5)   (Free)                          __________________________________________________________________________

Using the suitable starting compounds, the compounds as listed in Tables 36-2 to 36-9 are obtained in the same manner as Reference Example 2.

                                      TABLE 36-2                                   __________________________________________________________________________       #STR275##                                                                       -                                                                           Ref.                                                                               R.sup.5 (substitution     M.p. (° C.)                                                                    Crystalline form                            Ex. No. position) m A R.sup.4 R.sup.1 and R.sup.2 or NMR (salt)                                                   (solvent for recrystal.)                  __________________________________________________________________________       211 --(CH.sub.2).sub.3 CH.sub.3 (2)  --OCH.sub.3 (5) 2 --CH.sub.2 -- H                                              130.0-130.3  (Free) Yellow powder                                            (Ethyl acetate-n-hexane)                     - 212 --CH.sub.2 CH.sub.3 (2)  --OCH.sub.3 (5) 2 --CH.sub.2 -- H                                                   193-196  (Free) Pale yellow                                                  needles  (Ethyl acetate-n-hexane)                                                - 213 --(CH.sub.2).sub.3 CH.sub.3                                            (2)  --OCH.sub.3 (3) 2 --CH.sub.2 --                                           H                                                                                NMR (19)  (Free) Yellow powder                                                 - 214 --CH.sub.3 (2)  --OCH.sub.3                                            (3) 2 --CH.sub.2 -- H                                                            NMR (39)  (Free) Yellow powder                                                 - 215 --OCH.sub.3 (3) 1 --CH.sub.2                                           -- H                                                                             190-191  (Free) Pale yellow powder         - 216 --OCH.sub.3 (3) 1                                                                                            H TR281##                                                                      NMR (42)  (Free) Orange oil                                                    - 217                                                                          2 --CH.sub.2 -- H                                                              148-149  (Free) Pale yellow powder                                            (Ethanol-n-hexane)                       __________________________________________________________________________

                                      TABLE 36-3                                   __________________________________________________________________________       #STR285##                                                                       -                                                                           Ref.                                                                               R.sup.5 (substitution                                                                              M.p. (° C.)                                                                    Crystalline form                                  Ex. No. position) m A R.sup.4 R.sup.1 and R.sup.2 or NMR (salt)                                             (solvent for recrystal.)                        __________________________________________________________________________       218                                                                                                           2 TR286##                                                                    --CH.sub.2 -- H                                                                  126-128  (Free) Pale yellow powder                                           (Ethanol-n-hexane)                                 - 219 --(CH.sub.2).sub.2 CH.sub.3 (2)  --OCH.sub.3 (5) 2 --CH.sub.2 --                                     H                                                                                140-142  (Free) Pale orange powder                                           (Ethanol)                                          - 220 --CH.sub.3 (2)  --OCH.sub.3 (5) 2 --CH.sub.2 -- H                                                      NMR (52)  (Free) Yellow powder                   - 221 --CH(CH.sub.3).sub.2 (2)  --OCH.sub.3 (5) 2 --CH.sub.2 -- H                                            NMR (53) Pale red powder                         - 222 --(CH.sub.2).sub.5 CH.sub.3 (2)  --OCH.sub.3 (5) 2 --CH.sub.2 --                                     H                                                                                NMR (54) White powder                            - 223 --OCH.sub.3 (2 & 5) 2 --CH.sub.2 -- H                                                                  NMR (61)  (Free) Pale brown powder            __________________________________________________________________________

                  TABLE 36-4                                                       ______________________________________                                          ##STR293##                                                                    ______________________________________                                         Reference Example 224                                                           ##STR294##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.19 : --OCH.sub.3 (4-position)                                                         #STR295##                                                          - M.p. 197.0-197.5° C. Crystalline form: Yellow powder               Solvent for recrystallization: Ethyl acetate-dimethylform-                                                Form: Free                                          Reference Example 225                                                           ##STR296##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                           R.sup.19 : --OCH.sub.3 (4-position)                                                         R.sup.5 : --OCH.sub.2 CH═CH.sub.2 (3-position)                  M.p. 130-132° C. Crystalline form: Pale yellow powder                 Solvent for recrystallization: Ethyl acetate-n-hexane                                                     Form: Free                                          Reference Example 226                                                           ##STR297##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.19 : --OCH.sub.3 (4-position                                                          #STR298##                                                          - M.p. 131.5-132.5° C. Crystalline form: White powder                Solvent for recrystallization: n-Hexane-ethyl acetate-dichloromethane           Form: Free                                                                      Reference Example 227                                                         # RTR299##                                                                      .sup.4 : H A: --CH.sub.2 -- m: 1                                               R.sup.19 : --OCH.sub.3 (4-position)                                                         #STR300##                                                          - M.p. 169.9-170.3° C. Crystalline form: Pale yellow powder          Solvent for recrystallization: Ethyl acetate-n-hexane                                                     Form: Free                                          ______________________________________                                    

                  TABLE 36-5                                                       ______________________________________                                         Reference Example 228                                                                                                RSTR301##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 2                                                 -                                        R.sup.19 : --OCH.sub.3 (4-position)                                                R.sup.5 : --(CH.sub.2).sub.2 CH.sub.3 (2-position) & --OCH.sub.3               (3-position)                                                                       M.p. 147.0-147.5° C.                                                                    Crystalline form: Pale yellow powder                   Solvent for recrystalization: Ethyl acetate n-hexane                                                     Form: Free                                           Reference Example 229                                                                                                RSTR302##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1             R.sup.19 : --OCH.sub.3 (4-position)                                                            #STR303##                                                       - M.p. 142.0-143.0° C. Crystalline form: White powder                Solvent for recrystallization: Ethyl acetate-n-hexane                                                    Form: Free                                           Reference Example 230                                                                                                RSTR304##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                                                 -                                        R.sup.19 : --OCH.sub.3 (4-position)                                                            R.sup.5 : --SCH.sub.3 (3-position)                             NMR 922)      Crystalline form: Pale yellow powder                               Form: Free                                                                   Reference Example 231                                                                                                RSTR305##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 2                                                 -                                        R.sup.19 : --OCH.sub.3 (4-position)                                              R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (2-position) & --OCH.sub.3             (3-position)                                                                       NMR (27)      Crystalline form: Pale yellow powder                           Form: Free                                                                   ______________________________________                                    

                  TABLE 36-6                                                       ______________________________________                                         Reference Example 232                                                           ##STR306##     R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                   -                                                                           R.sup.19 : --OCH.sub.3 (4-position)                                              R.sup.5 : --CH.sub.3 (2-position) & --OCH.sub.3 (3-position)                     NMR (35)       Crystalline form: Orange powder                               Form: Free                                                                   Reference Example 233                                                           ##STR307##     R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                   -                                                                           R.sup.19 : --OCH.sub.3 (4-position)                                              R.sup.5 : --CH.sub.3 (2-position) & --OCH.sub.3 (3-position)                     NMR (36)       Crystalline form: Orange powder                             Reference Example 234                                                           ##STR308##     R                                                                             .sup.4 : H A: --(CH.sub.2).sub.3 -- m: 2                           -                                                                           R.sup.19 : --OCH.sub.3 (4-position)                                                                R.sup.5 : --OCH.sub.3 (3-position)                         M.p. 186-188° C.                                                                       Crystalline form: White powder                                    Form: Free                                                                   Reference Example 235                                                           ##STR309##     R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                   -                                                                           R.sup.19 : --OCH.sub.3 (4-position)                                              R.sup.5 : --CH.sub.2 CH═CH.sub.2 (2-position) & --OCH.sub.3              (5-position)                                                                       M.p. 187-189° C.                                                                       Crystalline form: Pale yellow powder                          Form: Free                                                                   ______________________________________                                    

                  TABLE 36-7                                                       ______________________________________                                         Reference Example 236                                                                                              RSTR310##                                                                    .sup.4: H A: --CH.sub.2 -- m: 2                                                  -                                          R.sup.19 : --OCH.sub.3 (4-position)                                              R.sup.5 : --OCH.sub.3 (2-position) & --N(CH.sub.3).sub.2 (3-position)          NMR (46)    Crystalline form: White powder                                                  Form: Free                                                      Reference Example 237                                                                                              RSTR311##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                                                  -                                          R.sup.19 : --OCH.sub.3 (4-position)                                              R.sup.5 : --N(CH.sub.3).sub.2 (2-position)                                     NMR (65)    Crystalline form: White powder                                     Form: Free                                                                   ______________________________________                                    

                  TABLE 36-8                                                       ______________________________________                                          ##STR312##                                                                    ______________________________________                                         Reference Example 238                                                                                              RSTR313##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                                                  -                                          R.sup.19 : --OCH.sub.3 (4-position)                                                          R.sup.5 : --OCH.sub.3 (3-position)                               T: --CH.sub.2 --                                                                         u: 1                                                                 NMR (48)  Crystalline form: White powder                                         Form: Free                                                                   ______________________________________                                    

                  TABLE 36-9                                                       ______________________________________                                          ##STR314##                                                                    ______________________________________                                         Reference Example 239                                                                                              RSTR315##                                                                    .sup.4: H A: --(CH.sub.2).sub.2 -- m: 1         -                                                                           R.sup.19 : --OCH.sub.3 (4-position)                                                          R.sup.5 : H                                                      NMR (73)  Crystalline form: Yellow powder                                        Form: Free                                                                   Reference Example 240                                                                                              RSTR316##                                                                    .sup.4: H A: --(CH.sub.2).sub.2 -- m: 1         -                                                                           R.sup.19 : --OCH.sub.3 (4-position)                                              R.sup.5 : --OCH.sub.3 (3-position)                                             NMR (75)    Crystalline form: Yellow powder                                    Form: Free                                                                   ______________________________________                                    

Using the suitable starting compounds, the compounds as listed in Table 36-10 to 36-16 are obtained in the same manner as in Reference Example 3.

                  TABLE 36-10                                                      ______________________________________                                          ##STR317##                                                                    ______________________________________                                         Reference Example 241                                                                                              RSTR318##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                                                  -                                          --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : --OCH.sub.2 CH═CH.sub.2 (3-position)                             M.p. 134-135° C.                                                                    Crystalline form: White powder                                   Solvent for recrystallization: Ethyl acetate-n-hexane                                                    Form: Free                                           Reference Example 242                                                                                              RSTR319##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                                                  -                                          --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                      -                                                                               #STR320##                                                                     -  NMR (8)     Crystalline form: Yellow oil                                   Form: Free                                                                   Reference Example 243                                                                                              RSTR321##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                                                  -                                          --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                      -                                                                               #STR322##                                                                     -  NMR (10)    Crystalline form: Yellow oil                                   Form: Free                                                                   ______________________________________                                    

                  TABLE 36-11                                                      ______________________________________                                         Reference Example 244                                                           # RTR323##                                                                      .sup.4: H A: --CH.sub.2 -- m: 2                                                 -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : --(CH.sub.2).sub.2 CH.sub.3 (2-position) & --OCH.sub.3             (3-position)                                                                     M.p. 156.5-157.4° C.                                                                  Crystalline form: White needles                                Solvent for recrystallization: Ethyl acetate-n-hexane                                                     Form: Free                                          Reference Example 245                                                           # RTR324##                                                                      .sup.4: H A: --CH.sub.2 -- m: 1                                                 -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                      -                                                                               #STR325##                                                                     -  NMR (16)   Crystalline form: Yellow amorphous                                                                 Form: Free                                Reference Example 246                                                           # RTR326##                                                                      .sup.4: H A: --CH.sub.2 -- m: 1                                                 -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : --SCH.sub.3 (3-position)                                             NMR (23) Crystalline form: Pale brown powder                                                                    Form: Free                                  Reference Example 247                                                           # RTR327##                                                                      .sup.4: H A: --CH.sub.2 -- m: 2                                                 -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (2-position) & --OCH.sub.3             (3-position)                                                                     NMR (28) Crystalline form: White powder                                                                         Form: Free                                  ______________________________________                                    

                  TABLE 36-12                                                      ______________________________________                                         Reference Example 248                                                           # RTR328##                                                                      .sup.4: H A: --CH.sub.2 -- m: 2                                                 -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : --CH.sub.3 (2-position) & --COCH.sub.3 (3-position)                  NMR (37)    Crystalline form: Pale red powder                                                                   Form: Free                                  Reference Example 249                                                           # RTR329##                                                                      .sup.4: H A: --CH.sub.2 -- m: 2                                                 -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : --CH.sub.2 CH.sub.3 (2-position) & --OCH.sub.3 (3-position)          NMR (38)    Crystalline form: Pale red powder                                                                   Form: Free                                  Reference Example 250                                                           # RTR330##                                                                      .sup.4: H A: --(CH.sub.2).sub.3 -- m: 1                                         -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --OCH.sub.2 PO(OCH.sub.3).sub.2              (4-position)                                                                     R.sup.5 : --OCH.sub.3 (3-position)                                             M.p. 140-142° C.                                                                       Crystalline form: Colorless prisms                            Solvent for recrystallization: Ethanol                                                                    Form: Free                                          Reference Example 251                                                           # RTR331##                                                                      .sup.4: H A: --CH.sub.2 -- m: 2                                                 -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : --CH.sub.2 CH═CH.sub.2 (2-position) & --OCH.sub.3              (5-position)                                                                     M.p. 125-128° C.                                                                       Crystalline form: Pale brown prisms                           Solvent for recrystallization: Ethanol-n-hexane                                                           Form: Free                                          ______________________________________                                    

                  TABLE 36-13                                                      ______________________________________                                         Reference Example 252                                                           # RTR332##                                                                      .sup.4: H A: --CH.sub.2 -- m: 2                                                 -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : -COCH.sub.2 PO(OCH.sub.3).sub.2              (4-position)                                                                     R.sup.5 : --OCH.sub.3 (2-position) & --N(CH.sub.3).sub.2 (3-position)          NMR (47) Crystalline form: Pale yellow powder                                                                Form: Free                                     Reference Example 253                                                           # RTR333##                                                                      .sup.4: H A: --CH.sub.2 -- m: 2                                                 -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : --Br (2-position) & --OCH.sub.3 (5-position)                         M.p. 196-199° C.                                                                      Crystalline form: White powder                                 Solvent for recrystallization: Ethanol                                                                 Form: Free                                             Reference Example 254                                                           # RTR334##                                                                      .sup.4: H A: --CH.sub.2 -- m: 1                                                 -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : --N(CH.sub.3).sub.2 (2-position)                                     NMR (66) Crystalline form: Yellow oil                                                                        Form: Free                                     Reference Example 254A                                                          # RTR335##                                                                      .sup.4: H A: --CH.sub.2 -- m: 1                                                 -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : --OCH.sub.3 (2-position)                                             NMR (77) Crystalline form: White powder                                                                      Form: Free                                     ______________________________________                                    

                                      TABLE 36-14                                  __________________________________________________________________________      ##STR336##                                                                    __________________________________________________________________________     Reference Example 255                                                           ##STR33 R#                                                                            .sup.4: H A: --CH.sub.2 -- m: 1                                           -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --OCH.sub.2 PO(OCH.sub.3).sub.2              (4-position)                                                                   R.sup.5 : --OCH.sub.3 (3-position)                                                        T: --CH.sub.2 --                                                                         u: 1                                                      NMR (49)                                                                            Crystalline form: Brown oil                                                                    Form: Free                                                __________________________________________________________________________

                  TABLE 36-15                                                      ______________________________________                                          ##STR338##                                                                    ______________________________________                                         Reference Example 256                                                           # RTR339##                                                                      .sup.4: H A: --(CH.sub.2).sub.2 -- m: 1                                         -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : H                                                                    NMR (74) Crystalline form: Pale brown oil                                                                       Form: Free                                  Reference Example 257                                                           # RTR340##                                                                      .sup.4: H A: --(CH.sub.2).sub.2 -- m: 1                                         -                                                                           --COCH.sub.2 PO(R.sup.18).sub.2 : --COCH.sub.2 PO(OCH.sub.3).sub.2             (4-position)                                                                     R.sup.5 : --OCH.sub.3 (3-position)                                             NMR (76) Crystalline form: Yellow powder                                                                       Form: Free                                   ______________________________________                                    

Using the suitable starting compounds, the compounds as listed in Table 36-16 are obtained in the same manner as in Reference Example 5 or 6.

                                      TABLE 36-16                                  __________________________________________________________________________      ##STR341##                                                                    __________________________________________________________________________     Reference Example 258                                                           ##STR34 R#                                                                            .sup.4: H A: --CH.sub.2 -- m: 2                                           -                                                                           R.sup.5 : --OCH.sub.3 (2 & 3-positions)                                        NMR (67)                                                                            Crystalline form: Pale yellow amorphous                                                           Form: Free                                             Reference Example 259                                                           ##STR34 R#                                                                            .sup.4: H A: --CH.sub.2 -- m: 1                                           -                                                                           R.sup.5 : --O(CH.sub.2).sub.3 Cl (3-position)                                  NMR (68)                                                                            Crystalline form: Colorless amorphous                                                             Form: Free                                             Reference Example 260                                                           ##STR34 R#                                                                            .sup.4: H A: --CH.sub.2 -- m: 1                                           -                                                                             #STR345##                                                                       -                                                                           NMR (69)                                                                            Crystalline form: Pale yellow amorphous                                                           Form: Free                                             Reference Example 261                                                           ##STR34 R#                                                                            .sup.4: H A: --CH.sub.2 -- m: 1                                           -                                                                           R.sup.5 : --OCH.sub.3 (3-position)                                             NMR (70)                                                                            Crystalline form: Dark brown amorphous                                                            Form: Free                                             __________________________________________________________________________

Using the suitable starting compounds, the compounds as listed in Table 36-17 are obtained in the same manner as in Reference Example 7, 8 or 9.

                  TABLE 36-17                                                      ______________________________________                                         Reference Example 262                                                           # STR347##                                                                       -                                                                           Colorless oil                                                                    Form: Free                                                                     NMR (71)                                                                       Reference Example 263                                                         # STR348##                                                                       -                                                                           Pale yellow oil                                                                  Form: Free                                                                     NMR (72)                                                                     ______________________________________                                    

Using the suitable starting compounds, the compounds as listed in Tables 36-18 to 36-21 are obtained in the same manner as in Reference Example 187.

                  TABLE 36-18                                                      ______________________________________                                          ##STR349##                                                                    ______________________________________                                         Reference Example 264                                                            R.sup.5 : --OH (3-position)                                                                     A: --CH.sub.2 --                                                                            m: 1                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (1)                                                                               Crystalline form: White solid                                                                          Form: Free                                      Reference Example 265                                                           # A: 350##                                                                      --CH.sub.2 -- m: 1                                                              -                                                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (2)                                                                               Crystalline form: White solid                                                                          Form: Free                                      Reference Example 266                                                            R.sup.5 : --OCH.sub.2 CH═CH.sub.2 (3-position)                                                  A: --CH.sub.2 --                                                                            m: 1                                       --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (4)                                                                               Crystalline form: Colorless oil                                                                        Form: Free                                      Reference Example 267                                                           # A: 351##                                                                      --CH.sub.2 -- m: 1                                                              -                                                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (6)                                                                               Crystalline form: Yellow oil                                                                           Form: Free                                      Reference Example 268                                                           # A: 352##                                                                      --CH.sub.2 -- m: 1                                                              -                                                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (9)                                                                               Crystalline form: Colorless oil                                                                        Form: Free                                      Reference Example 269                                                            R.sup.5 : --CH.sub.2 CH═CH.sub.2 (2-position) & --OH (3-position)              A: --CH.sub.2 --  m: 2                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    M.p. 93.1-93.8° C                                                                       Crystalline form: Colorless needles                            Solvent for recrystallization: n-Hexane-ethyl acetate                                                     Form: Free                                          Reference Example 270                                                            R.sup.5 : --(CH.sub.2).sub.2 CH.sub.3 (2-position) & --OH (3-position)             A: --CH.sub.2 --  m: 2                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (12)                                                                              Crystalline form: White solid                                                                          Form: Free                                      ______________________________________                                    

                  TABLE 36-19                                                      ______________________________________                                         Reference Example 271                                                            R.sup.5 : --(CH.sub.2).sub.2 CH.sub.3 (2-position) & --OCH.sub.3               (3-position)                                                                       A: --CH.sub.2 --  m: 2                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (13)                                                                              Crystalline form: Colorless oil                                                                        Form: Free                                      Reference Example 272                                                           # A: 353##                                                                      --CH.sub.2 -- m: 1                                                              -                                                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (15)                                                                              Crystalline form: Colorless oil                                                                        Form: Free                                      Reference Example 273                                                            R.sup.5 : --SCH.sub.3 (3-position)                                                                     A: --CH.sub.2 --                                                                         m: 1                                       --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (20)                                                                              Crystalline form: Pale yellow powder                                                                   Form: Free                                      Reference Example 274                                                            R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (2-position) & --OH (3-position)             A: --CH.sub.2 --  m: 2                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (24)                                                                              Crystalline form: Pale brown powder                                                                    Form: Free                                      Reference Example 275                                                            R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (2-position) & --OCH.sub.3               (3-position)                                                                       A: --CH.sub.2 --  m: 2                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (25)                                                                              Crystalline form: White powder                                                                         Form: Free                                      Reference Example 276                                                            R.sup.5 : --CH.sub.2 CH.sub.3 (2-position) & --OH (3-position)                     A: --CH.sub.2 --  m: 2                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (29)                                                                              Crystalline form: White powder                                                                         Form: Free                                      Reference Example 277                                                            R.sup.5 : --CH.sub.3 (2-position) & --OH (3-position)                              A: --CH.sub.2 --  m: 2                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (30)                                                                              Crystalline form: White powder                                                                         Form: Free                                      ______________________________________                                    

                  TABLE 36-20                                                      ______________________________________                                         Reference Example 278                                                            R.sup.5 : --CH.sub.3 (2-position) & --OCH.sub.3 (3-position)                       A: --CH.sub.2 --  m: 2                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (31)                                                                              Crystalline form: Colorless needles                                                                    Form: Free                                      Reference Example 279                                                            R.sup.5 : --CH.sub.2 CH.sub.3 (2-position) & --OCH.sub.3 (3-position)              A: --CH.sub.2 --  m: 2                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (32)                                                                              Crystalline form: Colorless oil                                                                        Form: Free                                      Reference Example 280                                                            R.sup.5 : --OH (3-position)                                                        A: --CH.sub.2 --  m: 1                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OC.sub.2 H.sub.5                             NMR (40)                                                                              Crystalline form: Colorless oil                                                                        Form: Free                                      Reference Example 281                                                            R.sup.5 : --OCH.sub.3 (3-position)                                                 A: --CH.sub.2 --  m: 1                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OC.sub.2 H.sub.5                             NMR (41)                                                                              Crystalline form: Pale brown powder                                                                    Form: Free                                      Reference Example 282                                                            R.sup.5 : --OCH.sub.3 (3-position)                                                 A: --(CH.sub.2).sub.3 --                                                                         m: 1                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    M.p. 48-50° C.                                                                          Crystalline form: White powder                                 Solvent for recrystallizafion: Ethyl acetate-n-hexane                                                     Form: Free                                          Reference Example 283                                                            R.sup.5 : --OCH.sub.3 (2-position) & --NH.sub.2 (3-position)                       A: --CH.sub.2 --  m: 2                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (44)                                                                              Crystalline form: Yellow oil                                                                           Form: Free                                      Reference Example 284                                                            R.sup.5 : --OCH.sub.3 (2-position) & --N(CH.sub.3).sub.2 (3-position)              A: --CH.sub.2 --  m: 2                                                   --COR.sup.19 : --COOCH.sub.3 (4-position)                                                           R.sup.24 : --OCH.sub.3                                    NMR (45)                                                                              Crystalline form: Brown oil                                                                            Form: Free                                      ______________________________________                                    

                                      TABLE 36-21                                  __________________________________________________________________________     Reference Example 285                                                          R.sup.5 : --Br (2-position) & --OH (5-position)                                A: --CH.sub.2 --                                                                             m: 2                                                             --COR.sup.19 : --COOCH.sub.3 (4-position)                                                         R.sup.24 : --OCH.sub.3                                      NMR (56)                                                                            Crystalline form: White powder                                                                     Form: Free                                            Reference Example 286                                                          R.sup.5 : --Br (2-position) & --OCH.sub.3 (5-position)                         A: --CH.sub.2 --                                                                             m: 2                                                             --COR.sup.19 : --COOCH.sub.3 (4-position)                                                         R.sup.24 : --OCH.sub.3                                      NMR (57)                                                                            Crystalline form: White powder                                                                     Form: Free                                            Reference Example 287                                                          R.sup.5 : --NH.sub.2 (2-position) & --OCH.sub.3 (5-position)                   A: --CH.sub.2 --                                                                             m: 2                                                             --COR.sup.19 : --COOCH.sub.3 (4-position)                                                         R.sup.24 : --OC.sub.2 H.sub.5                               NMR (59)                                                                            Crystalline form: White powder                                                                     Form: Free                                            Reference Example 288                                                          R.sup.5 : --N(CH.sub.3).sub.2 (2-position)                                     A: --CH.sub.2 --                                                                             m: 1                                                                - --COR.sup.19 : --COOCH.sub.3 (4-position)                                                    #STR354##                                                      -                                                                           NMR (63)                                                                            Crystalline form: Yellow oil                                                                       Form: Free                                            __________________________________________________________________________

Using the suitable starting compounds, the compounds as listed in Tables 36-22 to 36-23 are obtained in the same manner as in Reference Example 1 or 194.

                  TABLE 36-22                                                      ______________________________________                                          ##STR355##                                                                    ______________________________________                                         Reference Example 289                                                           # STR356##                                                                       -                                                                           A --CH.sub.2 --                                                                              m: 1   --COR.sup.19 : --COOCH.sub.3 (4-position)                 NMR (3)                                                                               Crystalline form: White solid                                                                          Form: Free                                      Reference Example 290                                                            R.sup.5 : --OCH.sub.2 CH═CH.sub.2 (3-position)                                 A: --CH.sub.2 --                                                                               m: 1 --COR.sup.19 : --COOCH.sub.3 (4-position)           NMR (5)                                                                               Crystalline form: White solid                                                                          Form: Free                                      Reference Example 291                                                            #STR357##                                                                      A: --CH.sub.2 --                                                                               m: 1   --COR.sup.19 : --COOCH.sub.3 (4-position)             NMR (7)                                                                               Crystalline form: Pale yellow oil                                                                      Form: Free                                      Reference Example 292                                                            #STR358##                                                                      A: --CH.sub.2 --                                                                               m: 1   --COR.sup.19 : --COOCH.sub.3 (4-position)             M.p. 124.5-126.0° C.                                                                  Crystalline form: White powder                                   Solvent for recrystallization: Ethyl acetate                                                              Form: Free                                          Reference Example 293                                                            R.sup.5 : --(CH.sub.2).sub.2 CH.sub.3 (2-position) & --OCH.sub.3               (3-position)                                                                       A: --CH.sub.2 --                                                                               m: 2 --COR.sup.19 : --COOCH.sub.3 (4-position)           NMR (14)                                                                              Crystalline form: White solid                                                                          Form: Free                                      Reference Example 294                                                            #STR359##                                                                      A: --CH.sub.2 --                                                                               m: 1   --COR.sup.19 : --COOCH.sub.3 (4-position)             M.p. 131.5-132.0° C.                                                                  Crystalline form: Pale yellow powder                             Solvent for recrystallization: Ethyl acetate                                                              Form: Free                                          Reference Example 295                                                            R.sup.5 : --SCH.sub.3 (3-position)                                                             A: --CH.sub.2 --  m: 1                                       --COR.sup.19 : --COOCH.sub.3 (4-position)                                                       NMR (21)                                                      Crystalline form: White powder                                                                            Form: Free                                          ______________________________________                                    

                  TABLE 36-23                                                      ______________________________________                                         Reference Example 296                                                            R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (2-position) & --OCH.sub.3             (3-position)                                                                     A: --CH.sub.2 --                                                               m: 2                                                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                      NMR (26)                                                                       Crystalline form: White powder                                                 Form: Free                                                                     Reference Example 297                                                          R.sup.5 : --CH.sub.3 (2-position) & --OCH.sub.3 (3-position)                   A: --CH.sub.2 --                                                               m: 2                                                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                      NMR (33)                                                                       Crystalline form: White powder                                                 Reference Example 298                                                          R.sup.5 : --CH.sub.2 CH.sub.3 (2-position) & --OCH.sub.3 (3-position)         A: --CH.sub.2 --                                                               m: 2                                                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                      NMR (34)                                                                       Crystalline form: White powder                                                 Reference Example 299                                                          R.sup.5 : --OCH.sub.3 (3-position)                                             A: --(CH.sub.2).sub.3 --                                                       m: 1                                                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                      M.p. 89-90° C.                                                          Crystalline form: Colorless needles                                            Solvent for recrystallization: Water-ethanol                                   Form: Free                                                                     Reference Example 300                                                          R.sup.5 : --CH.sub.2 CH═CH.sub.2 (2-position) & --OCH.sub.3 (5-positi     on)                                                                             A: --CH.sub.2 --                                                               m: 2                                                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                      NMR (43)                                                                       Crystalline form: White powder                                                 Form: Free                                                                     Reference Example 301                                                          R.sup.5 : --Br (2-position) & --OCH.sub.3 (5-position)                         A: --CH.sub.2 --                                                               m: 2                                                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                      NMR (58)                                                                       Crystalline form: White powder                                                 Form: Free                                                                     Reference Example 302                                                          R.sup.5 : --N(CH.sub.3).sub.2 (2-position)                                     A: --CH.sub.2 --                                                               m: 1                                                                           --COR.sup.19 : --COOCH.sub.3 (4-position)                                      NMR (64)                                                                       Crystalline form: White amorphous                                              Form: Free                                                                    ______________________________________                                    

Reference Example 303

Using the suitable starting compounds, the following compounds are obtained in the same manner as in Reference Example 6.

Methyl α-(2,3-dihydroxy-4-acetylphenoxy)acetate: White powder; ¹ H-NMR (DMSO-d₆) δppm: 2.56 (3H, s), 3.69 (3H, s), 4.91 (2H, s), 6.49 (1H, d, J=9.1 Hz), 7.35 (1H, d, J=9.1 Hz), 8.79 (1H, s), 12.31 (1H, s).

Methyl α-(2,3-dimethoxy-4-acetylphenoxy)acetate: White solid; ¹ H-NMR (CDCl₃) δppm: 2.60 (3H, s), 3.81 (3H, s), 3.93 (3H, s), 3.99 (3H, s), 4.75 (2H, s), 6.57 (1H, d, J=8.9 Hz), 7.48 (1H, d, J=8.9 Hz).

Methyl α-[2,3-dimethoxy-4-(2-bromoacetyl)phenoxy]acetate: Colorless oil; ¹ H-NMR (CDCl₃) δppm: 3.81 (3H, s), 3.93 (3H, s), 4.07 (3H, s), 4.57 (2H, s), 4.76 (2H, s), 6.58 (1H, d, J=8.9 Hz), 7.54 (1H, d, J=8.9 Hz).

(2,3-Dimethoxy-4-methoxycarbonylmethoxybenzoyl)methylenetriphenylphosphorane: Colorless amorphous; ¹ H-NMR (CDCl₃) δppm: 3.77 (3H, s), 3.94 (6H, s), 4.61 (1H, brd, J=27.8 Hz), 4.70 (2H, s), 6.56 (1H, d, J=8.8 Hz), 7.38-7.80 (16H, m).

Ethyl α-[3-(3-chloropropoxy)-4-acetylphenoxy)acetate: Yellow oil; ¹ H-NMR (CDCl₃) δppm: 1.31 (3H, t, J=7 Hz), 2.2-2.5 (2H, m), 2.57 (3H, s), 3.77 (2H, t, J=6.5 Hz). 4.30 (2H, t, J=7 Hz), 4.66 (2H, s), 6.47 (1H, dd, J=2H, J=8.5 Hz), 6.57 (1H, d, J=2 Hz), 7.81 (1H, d, J=8.5 Hz).

Ethyl α-[3-(3-chloropropoxy)-4-(2-bromoacetyl)phenoxy]acetate: Colorless oil; ¹ H-NMR (CDCl₃) δppm: 1.31 (3H, t, J=7 Hz), 2.25-2.55 (2H, m), 3.55-3.85 (2H, m), 4.15-4.4 (4H, m), 4.50 (2H, s), 4.68 (2H, s), 6.51 (1H, dd, J=2 Hz, J=9 Hz), 6.59 (1H, d, J=2 Hz), 7.89 (1H, d, J=9 Hz).

[2-(3-Chloropropoxy)-4-ethoxycarbonylmethoxybenzoyl]methylenetriphenylphosphorane: Pale brown amorphous; ¹ H-NMR (CDCl₃) δppm: 1.31 (3H, t, J=7 Hz), 2.2-2.7 (2H, m), 3.67 (2H, d, J=5.5 Hz), 4.27 (2H, q, J=7 Hz), 4.2-4.4 (2H, m), 4.66 (2H, s), 6.20 (1H, br), 6.47 (1H, dd, J=2 Hz, J=9 Hz), 6.57 (1H, d, J=2 Hz), 7.4-8.0 (16H, m).

(2,3-Dimethoxy-4-carboxymethoxybenzoyl)methyltriphenylphosphonium chloride: Colorless prisms (recrystallized from diluted hydrochloric acid); M.p. 137-151° C. (decomposed); ¹ H-NMR (DMSO-d₆) δppm: 3.78 (3H, s), 3.81 (3H, s), 4.69 (2H, s), 6.63 (1H, d, J=8.9 Hz), 7.28 (1H, d, J=8.9 Hz), 7.50-7.80 (15H, m).

[2-(3-Chloropropoxy)-4-carboxymethoxybenzoyl]methyltriphenylphosphonium chloride: Pale yellow amorphous; ¹ H-NMR (CDCl₃) δppm: 2.1-2.45 (2H, m), 3.63 (2H, t, J=6.5 Hz), 4.04 (2H, t, J=5 Hz), 4.49 (2H, s), 6.35 (1H, dd, J=2 Hz, J=7 Hz), 6.48 (1H, d, J=2 Hz), 7.35-7.9 (16H, m).

¹ H-NMR spectrum (NMR (1) to NMR (77)) as described in Tables 36-1 to 36-23 are as follows:

NMR (1) (CDCl₃) δppm: 3.81 (3H, s), 3.91 (3H, s), 4.65 (2H, s), 6.39 (1H, d, J=2.6 Hz), 6.45 (1H, dd, J=2.6 Hz, J=8.8 Hz), 7.73 (1H, d, J=8.8 Hz), 10.97 (1H, s); NMR (2) (CDCl₃) δppm: 3.80 (3H, s), 3.87 (3H, s), 4.64 (2H, s), 5.16 (2H, s), 6.42 (1H, dd, J=2.4 Hz, J=8.7 Hz), 6.60 (1H, d, J=2.4 Hz), 7.30-7.43 (3H, m), 7.49-7.52 (2H, m), 7.85 (1H, d, J=8.7 Hz); NMR (3) (DMSO-d₆) δppm: 3.76 (3H, s), 4.76 (2H, s), 5.19 (2H, s), 6.54 (1H, dd, J=2.3 Hz, J=8.7 Hz), 6.76 (1H, d, J=2.3 Hz), 7.27-7.44 (3H, m), 7.49-7.53 (2H, m), 7.69 (1H, d, J=8.7 Hz), 13.07 (1H, brs); NMR (4) (CDCl₃) δppm: 3.82 (3H, s), 3.86 (3H, s), 4.58-4.62 (2H, m), 4.66 (2H, s), 5.28-5.58 (2H, m), 5.98-6.19 (1H, m), 6.41 (1H, dd, J=2.4 Hz, J=8.7 Hz), 6.54 (1H, d, J=2.4 Hz), 7.83 (1H, d, J=8.7 Hz); NMR (5) (DMSO-d₆) δppm: 3.74 (3H, s), 4.59-4.63 (2H, m), 4.75 (2H, s), 5.21-5.29 (2H, m), 5.93-6.09 (1H, m), 6.52 (1H, dd, J=2.3 Hz, J=8.7 Hz), 6.64 (1H, d, J=2.3 Hz), 7.67 (1H, d, J=8.7 Hz), 13.05 (1H, brs); NMR (6) (CDCl₃) δppm: 1.52-2.00 (8H, m), 3.82 (3H, s), 3.84 (3H, s), 4.66 (2H, s), 4.73-4.84 (1H, m), 6.37 (1H, dd, J=2.4 Hz, J=8.7 Hz), 6.53 (1H, d, J=2.4 Hz), 7.79 (1H, d, J=8.7 Hz); NMR (7) (CDCl₃) δppm: 1.52-2.03 (8H, m), 3.84 (3H, s), 4.71 (2H, s), 4.30-5.20 (2H, m), 6.40 (1H, dd, J=2.4 Hz, J=8.7 Hz), 6.54 (1H, d, J=2.4 Hz), 7.80 (1H, d, J=8.7 Hz); NMR (8) (CDCl₃) δppm: 1.65-2.12 (8H, m), 3.74 (3H, s), 3.78 (3H, s), 3.70-3.88 (2H, m), 4.79 (2H, s), 4.83-4.94 (1H, m), 6.40-6.62 (2H, m), 7.32-7.4 (1H, m), 7.44-7.52 (1H, m), 7.79-7.90 (3H, m), 8.31-10.20 (1H, brs); NMR (9) (CDCl₃) δppm: 3.61 (3H, s), 3.81 (3H, s), 4.70 (2H, s), 6.83-6.97 (2H, m), 7.22-7.33 (2H, m), 7.33-7.45 (3H, m), 7.85 (1H, d, J=8.8 Hz); NMR (10) (CDCl₃) δppm: 3.50-3.70 (8H, m), 4.79 (2H, s), 6.77-6.97 (2H, m), 7.09-7.49 (8H, m), 7.58-7.89 (2H, m), 9.97-10.81 (1H, brs); NMR (11) (CDCl₃) δppm: 0.88 (3H, t, J=7.2 Hz), 1.26-1.47 (2H, m), 1.47-1.66 (2H, m), 2.56 (2H, t, J=7.5 Hz), 3.78 (3H, s), 4.66 (2H, s), 6.33 (1H, d, J=2.4 Hz), 6.46 (1H, dd, J=2.4 Hz, J=8.3 Hz), 7.05 (1H, d, J=8.3 Hz); NMR (12) (CDCl₃) δppm: 0.92 (3H, t, J=7.4 Hz), 1.48-1.70 (2H, m), 2.65-2.78 (2H, m), 3.79 (3H, s), 3.90 (3H, s), 4.70 (2H, s), 6.25 (1H, d, J=8.9 Hz), 7.65 (1H, d, J=8.9 Hz), 11.08 (1H, s); NMR (13) (CDCl₃) δppm: 0.94 (3H, t, J=7.3 Hz), 1.49-1.71 (2H, m), 2.63-2.77 (2H, m), 3.80 (3H, s), 3.83 (3H, s), 3.89 (3H, s), 4.70 (2H, s), 6.48 (1H, d, J=8.8 Hz), 7.70 (1H, d, J=8.8 Hz); NMR (14) (CDCl₃) δppm: 0.93 (3H, t, J=7.3 Hz), 1.47-1.70 (2H, m), 2.62-2.76 (2H, m), 3.83 (3H, s), 3.90 (3H, s), 4.74 (2H, s), 6.51 (1H, d, J=8.8 Hz), 7.20 (1H, brs), 7.72 (1H, d, J=8.8 Hz); NMR (15) (CDCl₃) δppm: 3.77 (3H, s), 3.79 (3H, s), 4.59 (2H, s), 6.45 (1H, d, J=2.5 Hz), 6.65 (1H, dd, J=2.5 Hz, J=8.8 Hz), 6.92-7.03 (2H, m), 7.03-7.17 (1H, m), 7.26-7.40 (2H, m), 7.91 (1H, d, J=8.8 Hz); NMR (16) (CDCl₃) δppm: 3.72 (3H, s), 3.77 (3H, s), 3.81 (2H, d, J=21.6 Hz), 4.68 (2H, s), 6.34 (1H, d, J=2.4 Hz), 6.62 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.04-7.15 (2H, m), 7.15-7.47 (5H, m), 7.68-7.83 (2H, m), 7.86 (1H, d, J=8.8 Hz), 10.65 (1H, brs); NMR (17) (DMSO-d₆) δppm: 2.02 (3H, s), 3.75 (3H, s), 4.64 (2H, s), 6.47 (1H, d, J=8.3 Hz), 6.60 (1H, d, J=8.3 Hz), 7.07 (1H, t, J=8.3 Hz), 12.93 (1H, brs); NMR (18) (DMSO-d₆) δppm: 0.86 (3H, t, J=7.2 Hz), 1.13-1.51 (4H, m), 2.59 (2H, t, J=7.6 Hz), 3.74 (3H, s), 4.63 (2H, s), 6.46 (1H, d, J=8.3 Hz), 6.59 (1H, d, J=8.3 Hz), 7.06 (1H, t, J=8.3 Hz), 12.89 (1H, brs); NMR (19) (CDCl₃) δppm: 0.97 (3H, t, J=7.1 Hz), 1.31-1.68 (4H, m), 2.77 (2H, t, J=7.0 Hz), 3.84 (3H, s), 4.75 (2H, s), 6.51 (1H, d, J=8.2 Hz), 6.64 (1H, d, J=8.2 Hz), 7.14 (1H, t, J=8.2 Hz), 7.26-7.39 (1H, m), 7.39-7.52 (1H, m), 7.73-7.90 (2H, m), 9.70 (1H, brs); NMR (20) (CDCl₃) δppm: 2.43 (3H, s), 3.82 (3H, s), 3.88 (3H, s), 4.70 (2H, s), 6.59 (1H, dd, J=8.8 Hz, J=2.4 Hz), 6.81 (1H, d, J=2.4 Hz), 8.00 (1H, d, J=8.8 Hz); NMR (21) (DMSO-d₆) δppm: 2.39 (3H, s), 3.77 (3H, s), 4.81 (2H, s), 6.62-6.83 (2H, m), 7.89 (1H, d, J=9.1 Hz), 13.14 (1H, brs); NMR (22) (CDCl₃) δppm: 2.48 (3H, s), 3.90 (3H, s), 4.82 (2H, s), 6.69 (1H, dd, J=8.7 Hz, J=2.4 Hz), 6.86 (1H, d, J=2.4 Hz), 7.36 (1H, dt, J=1.2 Hz, J=7.7 Hz), 7.48 (1H, dt, J=1.2 Hz, J=7.7 Hz), 7.84 (2H, t, J=7.7 Hz), 8.05 (1H, d, J=8.7 Hz), 9.91 (1H, brs); NMR (23) (CDCl₃) δppm: 2.41 (3H, s), 3.63 (2H, d, J=22.6 Hz), 3.80 (6H, d, J=11.2 Hz), 4.82 (2H, s), 6.71 (1H, dd, J=8.8 Hz, J=2.4 Hz), 6.85 (1H, d, J=2.4 Hz), 7.34 (1H, dt, J=1.3 Hz, J=9.2 Hz), 7.47 (1H, dt, J=1.3 H, J=9.2 Hz), 7.82 (2H, t, J=9.2 Hz), 8.01 (1H, d, J=8.8 Hz); NMR (24) (CDCl₃) δppm: 0.93 (3H, t, J=7.0 Hz), 1.19-1.62 (4H, m), 2.73 (2H, t, J=7.0 Hz), 3.79 (3H, s), 3.91 (3H, s), 4.70 (2H, s), 6.27 (1H, d, J=9.0 Hz), 7.67 (1H, d, J=9.0 Hz), 11.07 (1H, s); NMR (25) (CDCl₃) δppm: 0.94 (3H, t, J=7.2 Hz), 1.29-1.63 (4H, m), 2.72 2H, t, J=7.1 Hz), 3.80 (3H, s), 3.83 (3H, s), 3.89 (3H, s), 4.70 (2H, s), 6.50 (1H, d, J=8.8 Hz), 7.72 (1H, d, J=8.8 Hz); NMR (26) (DMSO-d₆) δppm: 0.88 (3H, t, J=7.1 Hz), 1.19-1.61 (4H, m), 2.60 (2H, t, J=6.7 Hz), 3.70 (3H, s), 3.78 (3H, s), 4.77 (2H, s), 6.71 (1H, d, J=8.8 Hz), 7.60 (1H, d, J=8.8 Hz), 13.05 (1H, brs); NMR (27) (CDCl₃) δppm: 0.99 (3H, t, J=7.1 Hz), 1.37-1.71 (4H, m), 2.80 (2H, t, J=6.9 Hz), 3.87 (3H, s), 3.91 (3H, s), 4.82 (2H, s), 6.66 (1H, d, J=8.8 Hz), 7.34 (1H, dt, J=1.3 Hz, J=7.7 Hz), 7.46 (1H, dt, J=1.3 Hz, J=7.7 Hz), 7.69-7.90 (3H, m), 9.62 (1H, brs); NMR (28) (CDCl₃) δppm: 1.00 (3H, t, J=7.0 Hz), 1.39-1.73 (4H, m), 2.78 (2H, t, J=8.0 Hz), 3.76 (6H, d, J=11.4 Hz), 3.79 (3H, s), 3.81 (2H, d, J=22.1 Hz), 4.82 (2H, s), 6.69 (1H, d, J=8.8 Hz), 7.34 (1H, t, J=8.6 Hz), 7.46 (1H, t, J=8.6 Hz), 7.57 (1H, d, J=8.8 Hz), 7.82 (2H, t, J=8.6 Hz), 9.87 (1H, brs); NMR (29) (CDCl₃) δppm: 1.14 (3H, t, J=7.5 Hz), 2.75 (2H, q, J=7.5 Hz), 3.80 (3H, s), 3.91 (3H, s), 4.71 (2H, s), 6.28 (1H, d, J=9.0 Hz), 7.67 (1H, d, J=9.0 Hz), 11.08 (1H, s); NMR (30) (CDCl₃) δppm: 2.18 (3H, s), 3.80 (3H, s), 3.91 (3H, s), 4.71 (2H, s), 6.28 (1H, d, J=9.0 Hz), 7.67 (1H, d, J=9.0 Hz), 11.11 (1H, s); NMR (31) (CDCl₃) δppm: 2.34 (3H, s), 3.81 (3H, s), 3.82 (3H, s), 3.89 (3H, s), 4.70 (2H, s), 6.51 (1H, d, J=8.8 Hz), 7.71 (1H, d, J=8.8 Hz); NMR (32) (CDCl₃) δppm: 1.18 (3H, t, J=7.5 Hz), 2.76 (2H, q, J=7.5 Hz), 3.80 (3H, s), 3.84 (3H, s), 3.89 (3H, s), 4.71 (2H, s), 6.51 (1H, d, J=8.8 Hz), 7.73 (1H, d, J=8.8 Hz); NMR (33) (DMSO-d₆) δppm: 2.10 (3H, s), 3.70 (3H, s), 3.78 (3H, s), 4.78 (2H, s), 6.72 (1H, d, J=8.9 Hz), 7.59 (1H, d, J=8.9 Hz), 13.11 (1H, brs); NMR (34) (DMSO-d₆) δppm: 1.08 (3H, t, J=7.4 Hz), 2.62 (2H, q, J=7.4 Hz), 3.72 (3H, s), 3.78 (3H, s), 4.79 (2H, s), 6.72 (1H, d, J=8.9 Hz), 7.60 (1H, d, J=8.9 Hz), 13.09 (1H, brs); NMR (35) (CDCl₃) δppm: 2.31 (3H, s), 3.85 (3H, s), 3.90 (3H, s), 4.82 (2s), 6.65 (1H, d, J=8.8 Hz), 7.34 (1H, dt, J=1.2 Hz, J=7.6 Hz), 7.46 (1H, dt, J=1.2 Hz, J=7.6 Hz), 7.69-7.89 (3H, m), 9.79 (1H, brs); NMR (36) (CDCl₃) δppm: 1.27 (3H, t, J=7.6 Hz), 2.83 (2H, q, J=7.6 Hz), 3.87 (3H, s), 3.91 (3H, s), 4.83 (2H, s), 6.66 (1H, d, J=8.8 Hz), 7.30 (1H, dt, J=1.3 Hz, J=7.3 Hz), 7.46 (1H, dt, J=1.3 Hz, J=7.3 Hz), 7.70-7.90 (3H, m), 9.72 (1H, brs); NMR (37) (CDCl₃) δppm: 2.33 (3H, s), 3.77 (6H, d, J=11.1 Hz), 3.80 (3H, s), 3.81 (2H, d, J=22.0 Hz), 4.82 (2H, s), 6.69 (1H, d, J=8.8 Hz), 7.35 (1H, dt, J=1.3 Hz, J=7.9 Hz), 7.47 (1H, dt, J=1.3 Hz, J=7.9 Hz), 7.61 (1H, d, J=8.8 Hz), 7.82 (2H, t, J=7.9 Hz), 9.87 (1H, brs); NMR (38) (CDCl₃) δppm: 1.29 (3H, t, J=7.5 Hz), 2.83 (2H, q, J=7.5 Hz), 3.76 (6H, d, J=11.2 Hz), 3.80 (2H, d, J=22.1 Hz), 3.81 (3H, s), 4.83 (2H, s), 6.70 (1H, d, J=8.8 Hz), 7.38 (1H, dt, J=1.4 Hz, J=8.6 Hz), 7.47 (1H, dt, J=1.4 Hz, 8.6 Hz), 7.59 (1H, d, J=8.8 Hz), 7.83 (2H, t, J=8.6 Hz), 9.73 (1H, brs); NMR (39) (CDCl₃) δppm: 2.24 (3H, s), 3.85 (3H, s), 4.75 (2H, s), 6.51 (1H, d, J=8.3 Hz), 6.63 (1H, d, J=8.3 Hz), 7.14 (1H, t, J=8.3 Hz), 7.29-7.40 (1H, m), 7.40-7.52 (1H, m), 7.74-7.91 (2H, m); NMR (40) (CDCl₃) δppm: 1.30 (3H, t, J=7 Hz), 3.91 (3H, s), 4.27 (2H, q, J=7 Hz), 4.63 (2H, s), 6.41 (1H, d, J=2.5 Hz), 6.48 (1H, dd, J=2.5 Hz, J=9 Hz), 7.75 (1H, d, J=9 Hz), 10.96 (1H, s); NMR (41) (CDCl₃) δppm: 1.30 (3H, t, J=7 Hz), 3.86 (3H, s), 3.89 (3H, s), 4.28 (2H, q, J=7 Hz), 6.43 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.58 (1H, d, J=2.5 Hz), 7.84 (1H, d, J=8.5 Hz); NMR (42) (CDCl₃) δppm: 1.69 (3H, d, J=7 Hz), 3.80 (3H, s), 4.95 (1H, q, J=7 Hz), 6.45-6.7 (3H, m), 7.15-7.5 (3H, m), 7.7-7.9 (2H, m), 9.77 (1H, br); NMR (43) (CDCl₃) δppm: 3.38 (2H, d, J=6.5 Hz), 3.84 (3H, s), 3.86 (3H, s), 4.74 (2H, s), 4.95-5.15 (2H, m), 5.85-6.1 (1H, m), 6.34 (1H, s), 7.69 (1H, s), 9.28 (1H, br); NMR (44) (CDCl₃) δppm: 3.80 (3H, s), 3.84 (3H, s), 3.88 (3H, s), 4.73 (2H, s), 5.98 (2H, br), 6.12 (1H, d, J=9 Hz), 7.59 (1H, d, J=9.1 Hz); NMR (45) (CDCl₃) δppm: 2.88 (6H, s), 3.80 (3H, s), 3.83 (3H, s), 3.87 (3H, s), 4.71 (2H, s), 6.48 (1H, d, J=8.7 Hz), 7.29 (1H, d, J=8.7 Hz); NMR (46) (CDCl₃) δppm: 2.91 (6H, s), 3.88 (3H, s), 3.89 (3H, s), 4.80 (2H, s), 6.64 (1H, d, J=8.7 Hz), 7.30-7.38 (2H, m), 7.42-7.51 (1H, m), 7.80-7.89 (2H, m), 10.24 (1H, br); NMR (47) (CDCl₃) δppm: 2.90 (6H, s), 3.69 (3H, s), 3.74 (2H, d, J=21.7 Hz), 3.75 (3H, s), 3.90 (3H, s), 4.83 (2H, s), 6.74 (1H, d, J=8.6 Hz), 7.26 (1H, d, J=8.6 Hz), 7.34 (1H, t, J=9.1 Hz), 7.43 (1H, t, J=9.1 Hz), 7.80-7.90 (2H, m), 10.10 (1H, br); NMR (48) (CDCl₃) δppm: 3.86 (3H, s), 3.89 (3H, s), 4.65 (2H, s), 4.97 (1H, d, J=5.9 Hz), 6.49-6.55 (2H, m), 7.34-7.54 (3H, m), 7.84-7.89 (1H, m), 7.98 (1H, d, J=7.3 Hz); NMR (49) (CDCl₃) δppm: 3.72 (3H, s), 3.78 (3H, s), 3.79 (2H, d, J=21.7 Hz), 3.92 (3H, s), 4.66 (2H, s), 4.97 (2H, d, J=5.9 Hz), 6.53-6.61 (2H, m), 7.39-7.54 (3H, m), 7.82-7.90 (2H, m), 7.98 (1H, d, J=7.6 Hz); NMR (50) (DMSO-d₆) δppm: 1.13 (6H, d, J=7.0 Hz), 3.08-3.35 (1H, m), 3.69 (3H, s), 4.66 (2H, s), 6.38 (1H, d, J=2.4 Hz), 6.48 (1H, d, J=2.4 Hz, J=8.4 Hz), 7.07 (1H, d, J=8.4 Hz), 12.93 (1H, s); NMR (51) (DMSO-d₆) δppm: 0.69-1.00 (3H, m), 1.08-1.62 (8H, m), 2.32-2.63 (2H, m), 3.68 (3H, s), 4.65 (2H, s), 6.30-6.53 (2H, m), 7.00 (1H, d, J=8.2 Hz), 12.92 (1H, s); NMR (52) (CDCl₃) δppm: 2.31 (3H, s), 3.78 (3H, s), 4.74 (2H, s), 6.42 (1H, d, J=2.4 Hz), 6.52 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.12 (1H, d, J=8.8 Hz), 7.25-7.53 (2H, m), 7.72-7.94 (2H, m), 9.71 (1H, s); NMR (53) (CDCl₃) δppm: 1.30 (6H, d, J=6.9 Hz), 3.19-3.46 (1H, m), 3.79 (3H, s), 4.75 (2H, s), 6.44 (1H, d, J=2.4 Hz), 6.60 (1H, dd, J=2.4 Hz, J=8.5 Hz), 7.20 (1H, d, J=8.5 Hz), 7.24-7.53 (2H, m), 7.72-7.94 (2H, m), 9.51-9.82 (1H, brs); NMR (54) (CDCl₃) δppm: 0.78-0.99 (3H, m), 1.18-1.77 (8H, m), 2.67 (2H, t, J=7.9 Hz), 3.78 (3H, s), 4.74 (2H, s), 6.43 (1H, d, J=2.4 Hz), 6.55 (1H, dd, J=2.4 Hz, J=8.3 Hz), 7.12 (1H, d, J=8.3 Hz), 7.23-7.52 (2H, m), 7.75-7.92 (2H, m), 9.56-9.80 (1H, brs); NMR (55) (DMSO-d₆) δppm: 2.09 (3H, s), 3.68 (3H, s), 4.66 (2H, s), 6.32-6.52 (2H, m), 7.02 (1H, d, J=8.1 Hz), 12.95 (1H, s); NMR (56) (CDCl₃) δppm: 3.82 (3H, s), 3.93 (3H, s), 4.73 (2H, s), 6.34 (1H, s), 8.02 (1H, s), 10.93 (1H, s); NMR (57) (CDCl₃) δppm: 3.82, 3.86, 3.88 (each 3H, each s), 4.77 (2H, s), 6.40 (1H, s), 8.07 (1H, d, J=3.1 Hz); NMR (58) (DMSO-d₆) δppm: 3.74, 3.82 (each 3H, each s), 4.97 (2H, s), 6.74 (1H, s), 7.85 (1H, d, J=3.6 Hz), 12.82-13.44 (1H, br); NMR (59) (DMSO-d₆) δppm: 3.73, 3.74 (each 3H, each s), 4.63 (2H, s), 6.76 (1H, s), 7.30 (1H, s), 10.66 (1H, brs); NMR (60) (DMSO-d₆) δppm: 3.66 (3H, s), 3.70 (3H, s), 4.64, 4.73 (total 1H, each s), 6.34-6.52 (2H, m), 6.79-6.96 (1H, m), 12.88-13.03 (1H, m); NMR (61) (CDCl₃) δppm: 3.77 (3H, s), 3.97 (3H, s), 4.78 (2H, s), 6.51-6.72 (2H, m), 6.89 (1H, d, J=8.8 Hz), 7.21-7.56 (2H, m), 7.73-7.92 (2H, m); NMR (62) DMSO-d₆) δppm: 1.27 (3H, t, J=7.0 Hz), 3.65 (3H, s), 3.92 (2H, q, J=7.0 Hz), 4.65 (2H, s), 6.32-6.52 (2H, m), 6.78-6.93 (1H, m), 12.81-13.01 (1H, brs); NMR (63) (CDCl₃) δppm: 2.84 (6H, s), 3.89 (3H, s), 4.81 (2H, s), 5.23 (2H, s), 6.70 (1H, d, J=9.0 Hz), 7.26-7.40 (5H, m), 7.60-7.64 (2H, m); NMR (64) (CDCl₃) δppm: 2.91 (6H, s), 3.93 (3H, s), 4.73 (2H, s), 7.14 (1H, d, J=7.8 Hz), 7.90-7.94 (2H, m), 9.72 (1H, br); NMR (65) (CDCl₃) δppm: 3.03 (6H, s), 3.91 (3H, s), 4.92 (2H, s), 7.12 (1H, d, J=8.3 Hz), 7.29 (1H, dt, J=1.2 Hz, J=7.8 Hz), 7.43 (1H, dt, J=1.2 Hz, J=7.8 Hz), 7.78-7.86 (4H, m), 13.22 (1H, br); NMR (66) (CDCl₃) δppm: 3.03 (6H, s), 3.61 (2H, d, J=22.7 Hz), 3.77 (3H, s), 3.81 (3H, s), 4.94 (2H, s), 7.15 (1H, d, J=8.4 Hz), 7.30 (1H, t, J=7.8 Hz), 7.43 (1H, t, J=7.8 Hz), 7.76-7.86 (4H, m); NMR (67) (CDCl₃) δppm: 3.96 (3H, s), 4.03 (3H, s), 4.55 (1H, brd, J=27.4 Hz), 4.76 (2H, s), 6.71 (1H, d, J=8.7 Hz), 7.25-7.38 (1H, m), 7.39-7.88 (19H, m), 10.50 (1H, brs); NMR (68) (CDCl₃) δppm: 2.10-2.30 (2H, m), 3.58 (2H, t, J=6.6 Hz), 4.04-4.19 (2H, m), 4.38-4.72 (1H, m), 4.65 (2H, s), 6.39 (1H, dd, J=2.3 Hz, J=8.6 Hz), 6.52 (1H, d, J=2.3 Hz), 7.28-7.95 (20H, m), 10.58 (1H, brs); NMR (69) (CDCl₃) δppm: 1.82-2.11 (2H, m), 2.11-2.38 (4H, m), 2.3-2.62 (2H, m), 3.49-3.75 (4H, m), 4.04 (2H, t, J=5.9 Hz), 4.50-4.93 (1H, m), 4.68 (2H, s), 6.40 (1H, dd, J=2.2 Hz, J=8.6 Hz), 6.54 (1H, d, J=2.2 Hz), 7.23-7.37 (1H, m), 7.37-7.62 (10H, m), 7.62-7.96 (9H, m), 10.37 (1H, brs); NMR (70) (CDCl₃) δppm: 3.00 (6H, s), 3.89 (3H, s), 4.70 (2H, s), 6.49 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.57 (1H, d, J=2.5 Hz), 6.93 (1H, dd, J=2.5 Hz, J=9 Hz), 7.08 (1H, d, J=2.5 Hz), 7.20-8.05 (16H, m), 8.55-8.65 (1H, m), 9.90 (1H, br); NMR (71) (CDCl₃) δppm: 1.21-1.56 (2H, m), 1.67 (1H, br), 1.75-1.94 (2H, m), 2.01 (1H, t, J=10.6 Hz), 2.01-2.89 (14H, m), 3.02-3.28 (2H, m), 3.55-3.78 (2H, m), 3.85-4.02 (1H, m); NMR (72) (CDCl₃) δppm: 1.83 (1H, br), 2.15 (1H, dd, J=4.1 Hz, J=12.8 Hz), 2.26 (6H, s), 2.43 (1H, dd, J=7.8 Hz, J=12.8 Hz), 2.53 (1H, dd, J=10.2 Hz, J=12.1 Hz), 2.68-2.98 (3H, m), 3.50-3.72 (2H, m), 3.78-3.99 (1H, m); NMR (73) (CDCl₃) δppm: 2.78 (2H, t, J=7.5 Hz), 3.09 (2H, t, J=7.5 Hz), 3.90 (3H, s), 7.15 (2H, d, J=8.5 Hz), 7.25-7.45 (2H, m), 7.68 (1H, d, J=7.5 Hz), 7.8-7.95 (1H, m), 7.90 (2H, d, J=8.5 Hz); NMR (74) (CDCl₃) δppm: 2.77 (2H, t, J=7.5 Hz), 3.06 (2H, t, J=7.5 Hz), 3.66 (2H, d, J=22.6 Hz), 3.75 (3H, s), 3.81 (3H, s), 7.10-7.22 (2H, m), 7.26-7.49 (2H, m), 7.63-7.68 (1H, m), 7.81-7.90 (3H, m); NMR (75) (CDCl₃) δppm: 2.79 (2H, t, J=7.5 Hz), 3.06 (2H, t, J=7.5 Hz), 3.76 (3H, s), 3.86 (3H, s), 6.65 (1H, d, J=8 Hz), 6.72 (1H, s), 7.25-7.5 (2H, m), 7.6-7.75 (2H, m), 7.85 (1H, d, J=7.5 Hz), 11.40 (1H, br); NMR (76) (CDCl₃) δppm: 2.80 (2H, t, J=7.5 Hz), 3.05 (2H, t, J=7.5 Hz), 3.73 (3H, s), 3.78 (3H, s), 3.79 (3H, s), 3.82 (2H, d, J=21.5 Hz), 6.65-6.8 (2H, m), 7.25-7.45 (2H, m), 7.60 (1H, d, J=8.5 Hz), 7.64 (1H, d, J=7.5 Hz), 7.82 (1H, dd, J=1 Hz, J=7.5 Hz), 11.49 (1H, br); NMR (77) (CDCl₃) δppm: 3.62 (2H, d, J=22.5 Hz), 3.77, 3.82 (6H, each s), 4.04 (3H, s), 4.85 (2H, s), 7.02 (1H, d, J=8.5 Hz), 7.3-7.55 (2H, m), 7.6-7.7 (2H, m), 7.8-7.9 (2H, m), 10.31 (1H, br).

Example 1

A solution of 2-(2-isopropylphenoxymethylcarbonylamino)benzothiazole (6.5 g), anhydrous maleic acid (3.9 g) and aluminum chloride (8.0 g) in 1,2-dichloroethane (50 ml) is stirred at room temperature for 7 hours. To the mixture is added water in order to decompose the aluminum chloride, and thereto is added ethyl acetate, and the mixture is stirred. The precipitated crystals are collected by filtration, washed with ethyl acetate, and dried to give a mixture (7.3 g) of a trans-compound and a cis-compound. The mixture thus obtained is dissolved in dimethylformamide (50 ml), and thereto is added conc. hydrochloric acid (1 ml), and the mixture is stirred at 60° C. for 30 minutes. To the mixture is added water (about 100 ml), and the precipitated crystals are collected by filtration, washed with methanol, and dried to give 2-[2-isopropyl-4-(trans-3-carboxyacryloyl)phenoxymethylcarbonylamino]benzothiazole (6.2 g).

¹ H-NMR (DMSO-d₆) δppm: 1.25 (6H, d, J=7 Hz), 3.40 (1H, sept, J=7 Hz), 5.12 (2H, s), 6.64 (1H, d, J=15.5 Hz), 7.03 (1H, d, J=8.5 Hz), 7.25-7.5 (2H, m), 7.77 (1H, d, J=7.5 Hz), 7.85-8.05 (4H, m), 12.70 (1H, br), 13.10 (1H, br).

Example 2

To a solution of 2-[2-isopropyl-4-(3-carboxyacryloyl)phenoxymethylcarbonylamino]benzothiazole (1.0 g) and triethylamine (0.4 ml) in dichloromethane (20 ml) is added dropwise isobutyl chloroformate (0.32 ml) under ice-cooling. To the mixture is added N-methylpiperazine (0.27 ml) at the same temperature, and the mixture is stirred for 2.5 hours. The reaction solution is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane→dichloromethane:methanol=30:1), and recrystallized from ethanol to give 2-{2-isopropyl-4-[3-(4-methyl-1-piperazinylcarbonyl)acryloyl]phenoxymethylcarbonylamino}benzothiazole (0.80 g).

Pale brown powder; M.p. 190-192° C.

Example 3

A solution of 2-[4-(3-carboxyacryloyl)phenoxymethylcarbonyamino]benzothiazole (1.0 g), thionyl chloride (0.23 ml) and a drop of dimethylformamide (20 ml) in dichloromethane (20 ml) is stirred at room temperature for 10 hours. The solution is added dropwise into a solution of 4-(4-methyl-1-piperazinyl)piperidine (0.5 g) and pyridine (1 ml) in dichloromethane (20 ml) under ice-cooling. To the reaction solution is added water, and the mixture is basified with 5% aqueous sodium hydroxide solution. The mixture is extracted with dichloromethane, and the extract is washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=50:1→10:1). The compound thus obtained is converted into a hydrochloride thereof by a conventional method and crystallized from ethanol-diethyl ether to give 2-[4-{3-[4-(4-methyl-1-piperazinyl)-1-piperidinylcarbonyl)acryloyl}phenoxymethylcarbonylamino]benzothiazole dihydrochloride (0.14 g).

White powder; M.p. 202.5-225° C. (decomposed); ¹ H-NMR (DMSO-d₆) δppm: 1.35-1.8 (2H, m), 2.0-2.3 (2H, m), 2.6-3.9 (11H, m), 2.81 (3H, s), 4.1-4.3 (1H, m), 4.5-4.7 (1H, m), 5.08 (2H, s), 7.15 (2H, d, J=9 Hz), 7.3-7.55 (3H, m), 7.76 (1H, d, J=14 Hz), 7.77 (1H, d, J=8.5 Hz), 7.98 (1H, d, J=8 Hz), 8.05 (2H, d, J=9 Hz), 12.67 (1H, br).

Example 4

To a solution of 2-[2-isopropyl-4-(3-carboxyacryloyl)phenoxymethylcarbonylamino]benzothiazole (0.97 g) in dimethylformamide (10 ml) are added dropwise 4-(4-methyl-1-piperazinyl)piperidine (0.65 g) and diethyl cyanophosphate (0.6 ml) at room temperature. To the mixture is added triethylamine (0.5 ml), and the mixture is stirred at room temperature for 10 minutes. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=100:1→10:1). The compound thus obtained is converted into a hydrochloride thereof in ethanol by a conventional method, and recrystallized from ethanol-diethyl ether to give 2-{2-isopropyl-4-[3-[4-(4-methyl-1-piperazinyl)-1-piperidinylcarbonyl]acryloyl]phenoxymethylcarbonylamino}benzothiazole dihydrochloride (0.45 g).

Yellow powder; M.p. 186-190° C. (decomposed).

Example 5

To a solution of dibutyl tartrate (4.0 g) in methanol (100 ml) is added a solution of sodium periodate (3.0 g) in water (30 ml), and the mixture is stirred for 10 minutes, and extracted with ethyl acetate. Separately, to a suspension of dimethyl {[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyl}phosphonate (5.7 g) in tetrahydrofuran (100 ml) is added a 5% aqueous sodium hydroxide solution under ice-cooling until the reaction solution becomes uniform, and then thereto is added dropwise a solution of glyoxalate, which is previously prepared from dibutyl tartrate, in tetrahydrofuran (30 ml) under ice-cooling. The mixture is stirred for 30 minutes, and acidified with 5% hydrochloric acid, and concentrated under reduced pressure to remove the tetrahydrofuran. The precipitated crystals are collected by filtration, and washed with dichloromethane. The dichloromethane layer is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=200:1) to give 2-[2-methoxy-4-(3-butoxycarbonylacryloyl)phenoxymethylcarbonylamino]benzothiazole (2.85 g), which is further stirred in tetrahydrofuran-5% aqueous sodium hydroxide solution at room temperature for 30 minutes to give 2-[2-methoxy-4-(3-carboxyacryloyl)phenoxymethylcarbonylamino]benzothiazole (2.9 g).

¹ H-NMR (DMSO-d₆) δppm: 3.89 (3H, s), 5.09 (2H, s), 6.67 (1H, d, J=15.5 Hz), 7.08 (1H, d, J=8.5 Hz), 7.25-7.55 (2H, m), 7.57 (1H, m), 7.7-8.1 (4H, m), 11.68 (1H, br).

Example 6

To a solution of ethyl propiolate (17.7 ml) in tetrahydrofuran (450 ml) is added dropwise a 1.71M solution of n-butyl lithium in n-hexane (102 ml) at -78° C., and the mixture is stirred for 10 minutes. To the solution is added dropwise a solution of 2-(2-methoxy-4-formylphenoxymethylcarbonylamino)benzothiazole (20 g) in tetrahydrofuran (400 ml) and N,N-dimethylpropylene urea (40 ml) at the same temperature over a period of 15 minutes. The mixture is further stirred for 10 minutes, and the reaction vessel is taken out from an iced bath, and further stirred for 20 minutes. To the mixture is added acetic acid (11 ml), and the mixture is diluted with ethyl acetate. The ethyl acetate layer is washed with a saturated aqueous sodium carbonate solution, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=100:1→50:1) to give 2-[2-methoxy-4-(3-methoxycarbonyl-1-hydroxypropargyl)phenoxymethylcarbonylamino]benzothiazole (33.7 g) as a dark brown oil.

To a solution of 2-[2-methoxy-4-(3-methoxycarbonyl-1-hydroxypropargyl)phenoxymethylcarbonylamino]benzothiazole (33.7 g) in dimethylformamide (150 ml) is added tri-n-butylamine (14.3 ml), and the mixture is stirred at room temperature for 1.5 hour. The mixture is diluted with ethyl acetate, and washed with 0.15N hydrochloric acid, and dried over sodium sulfate. The mixture is concentrated under reduced pressure to remove the solvent, and the precipitated crystals are collected by filtration to give 2-[2-methoxy-4-(trans-3-methoxycarbonylacryloyl)phenoxymethylcarbonylamino]benzothiazole (Compound A, 5.5 g) as pale yellow powder. On the other hand, the filtrate is concentrated under reduced pressure, and crystallized from ethanol-diethyl ether give 2-[2-methoxy-4-(cis-3-methoxycarbonylacryloyl)phenoxymethylcarbonylamino]benzothiazole (Compound B, 6.0 g) as pale yellow powder.

Compound A:

¹ H-NMR (DMSO-d₆) δppm: 1.26 (3H, t, J=7.1 Hz), 3.92 (3H, s), 4.21 (2H, q, J=7.1 Hz), 5.11 (2H, s), 6.71 (1H, d, J=15.5 Hz), 7.08 (1H, d, J=8.6 Hz), 7.31-7.37 (1H, m), 7.44-7.50 (1H, m), 7.59 (1H, d, J=2.0 Hz), 7.75-7.81 (2H, m), 7.98 (1H, d, J=15.5 Hz), 8.00-8.02 (1H, m), 12.67 (1H, brs).

Compound B:

¹ H-NMR (DMSO-d₆) δppm: 1.05 (3H, t, J=7.1 Hz), 3.89 (3H, s), 3.97 (2H, q, J=7.1 Hz), 5.11 (2H, s), 6.35 (1H, d, J=12.3 Hz), 7.05 (1H, d, J=8.8 Hz), 7.21 (1H, d, J=12.3 Hz), 7.31-7.37 (1H, m), 7.44-7.50 (3H, m), 7.78-7.81 (1H, m), 7.99-8.02 (1H, m), 12.62 (1H, brs).

Example 7

A solution of 2-{2-isopropyl-4-[trans-3-(4-methyl-1-piperazinyl)carbonylacryloyl]phenoxymethylcarbonylamino}benzothiazole (100 mg) in dimethylformamide (10 ml) is allowed to stand for 6.5 hours by a window in order to be exposed to direct sunlight. To the mixture is added water, the precipitated crystals are collected by filtration, and recrystallized from ethanol to give 2-{2-isopropyl-4-[cis-3-(4-methyl-1-piperazinyl)carbonylacryloyl]phenoxymethylcarbonylamino}benzothiazole (45 mg).

Pale yellow powder; M.p. 114-115° C.

Example 8

To a solution of dimethyl {[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyl}phosphonate (1.7 g) and pyridine-4-aldehyde (0.5 g) in tetrahydrofuran (30 ml) is added a 5% aqueous sodium hydroxide solution (6 ml) under ice-cooling, and the mixture is stirred for 5 hours. The mixture is neutralized with acetic acid, and the precipitated crystals are collected by filtration, and then recrystallized from dichloromethane-ethanol-diethyl ether to give 2-{2-methoxy-4-[3-(4-pyridyl)acryloyl]phenoxymethylcarbonylamino}benzothiazole (1.3 g).

Pale yellow powder; M.p. 206-207° C.

Example 9

To a solution of 2-[2-methoxy-4-(3-t-butoxycarbonyl-1-hydoxypropargyl)phenoxymethylcarbonylamino]benzothiazole (1 g) in chloroform (50 ml) is added active manganese dioxide (1 g), and the mixture is refluxed for two hours. To the mixture is further added active manganese dioxide (1 g), and the mixture is refluxed for 1.5 hour. The mixture is filtered through a cerite pad, and the filtrate is concentrated. The residue is recrystallized from ethanol to give 2-[2-methoxy-4-(3-t-butoxycarbonylpropiolyl)phenoxymethylcarbonylamino]benzothiazole (0.5 g).

Example 10

To a solution of 2-[2-methoxy-4-(3-t-butoxycarbonylpropioloyl)phenoxymethylcarbonylamino]benzothiazole (0.5 g) in methylene chloride (30 ml) is added trifluoroacetic acid (10 ml), and the mixture is stirred at room temperature for 4 hours. The mixture is concentrated, and to the residue is added methylene chloride. The mixture is stirred, and the precipitated crystals are collected by filtration, and recrystallized from dichloromethane-trifluoroacetic acid to give 2-[2-methoxy-4-(3-carboxypropioloyl)phenoxymethylcarbonylamino]-benzothiazole (0.26 g) as brown powder.

M.p. 174-176° C.

Using the suitable starting compounds, the following compounds are obtained in the same manner as in Example 1 or 5.

                                      TABLE 38                                     __________________________________________________________________________      ##STR360##                                                                    __________________________________________________________________________     Example 11                                                                     R.sup.4: H    A: --CH.sub.2 --                                                                         Z: O                                                   R.sup.5 : CH.sub.3 (2-position)                                                                        m: 1                                                   M.p. 261-262°0 C.                                                                       Crystalline form: Beige powder                                 Solvent for recrystallization: Dimethylformamide-methanol                        Form: Free                                                                     Example 12                                                                   R.sup.4: H    A: --CH.sub.2 --                                                                         Z: O                                                   R.sup.5 : C.sub.2 H.sub.5 (2-position)                                                                 m: 1                                                   M.p. 245-246°C.                                                                         Crystalline form: Beige powder                                 Solvent for recrystallization: Dimethylformamide-methanol                        Form: Free                                                                     Example 13                                                                   R.sup.4: H    A: --CH.sub.2 --                                                                         Z: O                                                   R.sup.5 : n-Propyl (2-position)                                                                        m: 1                                                     Crystalline form: Yellow powder Form: Free                                     NMR(1)                                                                       __________________________________________________________________________

                  TABLE 39                                                         ______________________________________                                         Example 14                                                                       R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : Isopropyl (2-position)                                               m: 1                                                                           M.p. 225-240° C. (decomp.)                                              Crystalline form: Yellow powder                                                NMR (2)                                                                        Solvent for recrystallization: Dimethylformamide-methanol                      Form: Free                                                                     Example 15                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : n-Butyl (2-position)                                                 m: 1                                                                           M.p. 187.5-190° C.                                                      Crystalline form: Pale yellow powder                                           Solvent for recrystallization: Chloroform-dimethylformamide                    Form: Free                                                                     Example 16                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : H                                                                    m: 1                                                                           M.p. 250-275° C. (decomp.)                                              Crystalline form: White powder                                                 NMR (3)                                                                        Solvent for recrystallization: Dimethylformamide-methanol                      Form: Free                                                                     Example 17                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : n-Pentyl (2-position)                                                m: 1                                                                           M.p. 139-163° C.                                                        Crystalline form: Pale yellow powder                                           NMR (4)                                                                        Solvent for recrystallization: Dimethylformamide-dichloromethane              Form: Free                                                                    ______________________________________                                    

                  TABLE 40                                                         ______________________________________                                         Example 18                                                                      R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : F (2-position)                                                       m: 1                                                                           M.p. 233-234° C.                                                        Crystalline form: Pale brown powder                                            Solvent for recrystallization: Dimethylformamide-methanol                      Form: Free                                                                     Example 19                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : Cl (2-position)                                                      m: 1                                                                           Crystalline form: Yellow powder                                                Form: Free                                                                     NMR (5)                                                                        Example 20                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : --(CH.sub.2).sub.4 (combined at 2- and 3-positions)                  m: 2                                                                           Crystalline form: Yellow powder                                                NMR (6)                                                                        Form: Free                                                                     Example 21                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : CH.sub.3 (2- and 3-positions)                                        m: 2                                                                           Crystalline form: Yellow powder                                                NMR (7)                                                                        Form: Free                                                                    ______________________________________                                    

                  TABLE 41                                                         ______________________________________                                         Example 22                                                                      R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : CH.sub.3 (2- and 6-positions)                                        m: 2                                                                           Crystalline form: Beige powder                                                 NMR (8)                                                                        Solvent for recrystallization: Dimethylformamide-methanol                      Form: Free                                                                     Example 23                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : CH.sub.3 (3- and 5-positions)                                        m: 2                                                                           Crystalline form: Yellow powder                                                Form: Free                                                                     NMR (9)                                                                        Example 24                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : --(CH.sub.2).sub.2 CO.sub.2 C.sub.2 H.sub.5 (2-position)             m: 1                                                                           M.p. 199.6-203.8° C.                                                    Crystalline form: Pale yellow powder                                           Solvent for recrystallization: Chloroform-dimethylformamide                    Form: Free                                                                     Example 25                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : --(CH.sub.2).sub.4 OCOCH.sub.3 (2-position)                          m: 1                                                                           M.p. 176-177.5° C.                                                      Crystalline form: Pale yellow powder                                           Solvent for recrystallization: Chloroform                                      Form: Free                                                                    ______________________________________                                    

                  TABLE 42                                                         ______________________________________                                         Example 26                                                                      R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : C.sub.2 H.sub.5 O (2-position)                                       m: 1                                                                           Crystalline form: Yellow powder                                                NMR (10)                                                                       Form: Free                                                                     Example 27                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : CH.sub.3 (3-position)                                                m: 1                                                                           M.p. 290° C. (decomp.)                                                  Crystalline form: White needles                                                NMR (11)                                                                       Solvent for recrystallization: Dimethylformamide                               Form: Free                                                                     Example 28                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : C.sub.2 H.sub.5 (3-position)                                         m: 1                                                                           Crystalline form: Yellow powder                                                NMR (12)                                                                       Form: Free                                                                     Example 29                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : n-Propyl (3-position)                                                m: 1                                                                           M.p. 282° C. (decomp.)                                                  Crystalline form: Pale brown needles                                           Solvent for recrystallization: Dimethylformamide-dichloromethane               Form: Free                                                                    ______________________________________                                    

                  TABLE 43                                                         ______________________________________                                         Example 31                                                                      R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : n-Butyl (3-position)                                                 m: 1                                                                           M.p. 267-279° C. (decomp.)                                              Crystalline form: Pink powder                                                  Form: Free                                                                     NMR (14)                                                                       Example 32                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : Isopropyl (3-position)                                               m: 1                                                                           M.p. 262.5-265.5° C.                                                    Crystalline form: Yellow powder                                                Solvent for recrystallization: Dimethylformamide-dichloromethane               Form: Free                                                                     Example 33                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : Cl (3-position)                                                      m: 1                                                                           Crystalline form: Pale yellow powder                                           NMR (15)                                                                       Form: Free                                                                    ______________________________________                                    

                  TABLE 44                                                         ______________________________________                                         Example 34                                                                                                 R                                                                             .sup.4 : H A: --CH.sub.2 -- Z: O                    R.sup.5 : F (3-position)                                                                              m: 1                                                      Crystalline form: Pale yellow powder NMR (16)                                  Form: Free                                                                   Example 35                                                                       R.sup.4 : H A: --CH.sub.2 -- Z: O                                            R.sup.5 : CH.sub.3 O (3-position)                                                                     m: 1                                                      Crystalline form: Yellow powder NMR (17)                                       Form: Free                                                                   Example 36                                                                       R.sup.4 : H A: --CH.sub.2 -- Z: O                                            R.sup.5 : C.sub.2 H.sub.5 O (3-position)                                                              m: 1                                                      Crystalline form: Yellow powder NMR (18)                                       Form: Free                                                                   Example 37                                                                       R.sup.4 : H m: 1 Z: O                                                           -                                                                             #STR361##                                                                       -                                                                               M.p. 294-295° C. (decomp.)                                                                Crystalline form: White powder                           Solvent for recrystallization: Dimethylformamide                                                        Form: Free                                            ______________________________________                                    

                  TABLE 45                                                         ______________________________________                                                Example 38                                                                R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : CH.sub.3 O (2-position)                                              m: 1                                                                           Crystalline form: Yellow powder                                                NMR (19)                                                                       Form: Free                                                                     Example 39                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : (CH.sub.3).sub.2 CHO-- (3-position)                                  m: 1                                                                           Crystaliine form: Pale yellow powder                                           NMR (20)                                                                       Form: Free                                                                     Example 40                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : CF.sub.3 CH.sub.2 O-- (3-position)                                   m: 1                                                                           Crystalline form: Pale yellow powder                                           NMR (21)                                                                       Form: Free                                                                     Example 41                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : CF.sub.3 (2-position)                                                m: 1                                                                           Crystalline form: Colorless powder                                             NMR (22)                                                                       Form: Free                                                                   ______________________________________                                    

                  TABLE 46                                                         ______________________________________                                         Example 42                                                                       R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : --OCH.sub.2 CON(C.sub.2 H.sub.5).sub.2 (2-position)                  m: 1                                                                           Crystalline form: Yellow powder                                                NMR (23)                                                                       Form: Free                                                                     Example 43                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 5; --COOCH.sub.3 (2-position)                                          m: 1                                                                           Crystalline form: Pale yellow powder                                           NMR (24)                                                                       Form: Free                                                                     Example 44                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : --(CH.sub.2).sub.2 --CONH-- (combined at 2- and 3-positions)        m: 2                                                                           Crystalline form: Yellow powder                                                NMR (25)                                                                       Form: Free                                                                     Example 45                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : (CH.sub.3).sub.3 C-- (2-position)                                    m: 1                                                                           M.p. 263-266° C. (decomp.)                                              Crystalline form: Yellow powder                                                Solvent for recrystallization: Dimethylformamide-dichloromethane               Form: Free                                                                    ______________________________________                                    

                  TABLE 47                                                         ______________________________________                                         Example 46                                                                      R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : --(CH.sub.2).sub.2 COOCH.sub.3 (2-position)                          m: 1                                                                           Crystalline form: Yellow powder                                                NMR (26)                                                                       Form: Free                                                                     Example 47                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : --(CH.sub.2).sub.2 CON(CH.sub.3).sub.2 (2-position)                  m: 1                                                                           Crystalline form: Pale yellow powder                                           NMR (27)                                                                       Form: Free                                                                     Example 48                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : --(CH.sub.2).sub.2 CON(C.sub.2 H.sub.5).sub.2 (2-position)           m: 1                                                                           Crystalline form: Yellow amorphous                                             NMR (28)                                                                       Form: Free                                                                     Example 49                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : Cl (2-position)                                                      m: 1                                                                           M.p. 235.5-237° C.                                                      Crystalline form: Yellow powder                                                Solvent for recrystallization: Dimethylformamide-water                         Form: Free                                                                    ______________________________________                                    

                  TABLE 48                                                         ______________________________________                                         Example 50                                                                      R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : --(CH.sub.2).sub.2 COOC.sub.2 H.sub.5 (2-position)                   m: 1                                                                           M.p. 199.6-203.8° C.                                                    Crystalline form: Pale yellow powder                                           Solvent for recrystallization: Chloroform-dimethylformamide                    Form: Free                                                                     NMR (29)                                                                       Example 51                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : n-Butyl (2-position)                                                 m: 1                                                                           M.p. 187.5-190° C.                                                      Crystalline form: Pale yellow powder                                           Solvent for recrystallization: Chloroform-dimethylformamide                    Form: Free                                                                     Example 52                                                                     R.sup.4 : H                                                                    A: --CH.sub.2 --                                                               Z: O                                                                           R.sup.5 : --(CH.sub.2).sub.4 OCOCH.sub.3 (2-position)                          m: 1                                                                           M.p. 176-177.5° C.                                                      Crystalline form: Pale yellow powder                                           Solvent for recrystallization: Chloroform                                      Form: Free                                                                    ______________________________________                                    

                  TABLE 49                                                         ______________________________________                                         Example 53                                                                                                 R                                                                             .sup.4 : H m: 1 Z: O                                   -                                                                             #STR362##                                                                       -                                                                               M.p. 285-287° C. (decomp.)                                                               Crystalline form: White powder                            Solvent for recrystallization: Dimethylformamide-water                           Form: Free                                                                       Example 54                                                                   R.sup.4 : H A: --CH.sub.2 -- Z: O                                            R.sup.5 : n-Heptyl (2-position)                                                                       m: 1                                                    M.p. 187-188.5° C.                                                                       Crystalline form: Pale yellow powder                          Solvent for recrystallization: Dichloromethane-dimethylformamide                 Form: Free                                                                       Example 55                                                                   R.sup.4 : H A: --CH.sub.2 -- Z: S                                            R.sup.5 : CH.sub.3 O (2-position)                                                                     m: 1                                                    M.p. 241-244° C.                                                                         Crystalline form: Yellow powder                                 Form: Free                                                                   ______________________________________                                    

¹ H-NMR spectrum (NMR (1) to NMR (29)) as described in Tables 38-49 are as follows:

NMR (1) (DMSO-d₆) δppm: 0.92 (3H, t, J=7.4 Hz), 1.58-1.69 (2H, m), 2.69 (2H, t, J=7.4 Hz), 5.12 (2H, s), 6.65 (1H, d, J=15.4 Hz), 7.03 (1H, d, J=8.6 Hz), 7.31 (1H, t, J=7.6 Hz), 7.44 (1H, t, J=7.7 Hz), 7.76 (1H, d, J=7.7 Hz), 7.87-7.99 (4H, m); NMR (2) (DMSO-d₆) δppm: 1.25 (6H, d, J=7 Hz), 3.40 (1H, sept, J=7 Hz), 5.12 (2H, s), 6.64 (1H, d, J=15.5 Hz), 7.03 (1H, d, J=8.5 Hz), 7.25-7.5 (2H, m), 7.77 (1H, d, J=7.5 Hz), 7.85-8.05 (4H, m), 12.70 (1H, br), 13.10 (1H, br); NMR (3) DMSO-d₆) δppm: 5.07 (2H, s), 6.65 (1H, d, J=15.5 Hz), 7.15 (2H, d, J=9 Hz), 7.1-7.5 (2H, m), 7.76 (1H, d, J=7 Hz), 7.89 (1H, d, J=15.5 Hz), 7.99 (1H, d, J=7 Hz), 8.05 (2H, d, J=9 Hz), 12.70 (1H, br), 13.04 (1H, br); NMR (4) DMSO-d₆) δppm: 0.89 (3H, t, J=6.4 Hz), 1.21-1.50 (4H,), 1.53-1.79 (2H, m), 2.69 (2H, t, J=8.0 Hz), 5.14 (2H, s), 6.64 (1H, d, J=15.5 Hz), 7.04 (1H, d, J=8.5 Hz), 7.30-7.38 (1H, m), 7.43-7.51 (1H, m), 7.78-7.82 (1H, d, J=7.9 Hz), 7.85-8.10 (4H, m); NMR (5) (DMSO-d₆) δppm: 5.22 (2H, s), 6.67 (1H, d, J=15.5 Hz), 7.24-7.49 (3H, m), 7.77 (1H, d, J=7.6 Hz), 7.89 (1H, d, J=15.5 Hz), 7.96-8.12 (3H, m), 12.83 (1H, br); NMR (6) DMSO-d₆) δppm: 1.6-1.9 (4H, m), 2.65-3.0 (4H, m), 5.06 (2H, s), 6.45 (1H, d, J=16 Hz), 6.82 (1H, d, J=8.5 Hz), 7.25-7.65 (4H, m), 7.75 (1H, d, J=8 Hz), 7.97 (1H, d, J=8 Hz), 12.85 (1H, br); NMR (7) (DMSO-d₆) δppm: 2.22 (3H, s), 2.31 (3H, s), 5.05 (2H, s), 6.44 (1H, d, J=15.5 Hz), 6.85 (1H, d, J=8.5 Hz), 7.25-7.6 (4H, m), 7.76 (1H, d, J=8 Hz), 7.98 (1H, d, J=8 Hz), 12.83 (1H, br); NMR (8) (DMSO-d₆) δppm: 2.36 (6H, s), 4.75 (2H, s), 6.67 (1H, d, J=15.5 Hz), 7.30-7.53 (2H, m), 7.77 (1H, d, J=8.9 Hz), 7.79 (2H, s), 7.91 (1H, d, J=15.5 Hz), 8.00 (1H, d, J=7.00 Hz), 12.09-13.2 (2H, br); NMR (9) (DMSO-d₆) δppm: 2.10 (6H, s), 4.95 (2H, s), 6.22 (1H, d, J=16 Hz), 6.78 (2H, s), 7.02 (1H, d, J=16 Hz), 7.25-7.5 (2H, m), 7.76 (1H, d, J=8 Hz), 7.98 (1H, d, J=7.5 Hz), 12.9 (2H, br); NMR (10) (CDCl₃) δppm: 1.37 (3H, d, J=7.0 Hz), 4.14 (2H, q, J=7.0 Hz), 5.09 (2H, s), 6.65 (1H, d, J=15.5 Hz), 7.06 (1H, d, J=8.6 Hz), 7.31 (1H, d, J=7.4 Hz), 7.44 (1H, t, J=7.4 Hz), 7.55 (1H, s), 7.67-7.78 (2H, m), 7.90 (1H, d, J=15.5 Hz), 7.98 (1H, d, J=7.4 Hz), 12.74 (2H, br); NMR (11) (DMSO-d₆) δppm: 2.45 (3H, s), 5.03 (2H, s), 6.45 (1H, d, J=15.6 Hz), 6.90-7.06 (2H, m), 7.28-7.35 (1H, m), 7.41-7.48 (1H, m), 7.56 (1H, d, J=15.6 Hz), 7.75 (2H, t, J=7.4 Hz), 7.97-8.00 (1H, m), 12.80 (2H, brs); NMR (12) DMSO-d₆) δppm: 1.13 (3H, t, J=7.4 Hz). 2.80 (2H, q, J=7.4 Hz), 5.03 (2H, s), 6.47 (1H, d, J=15.6 Hz), 6.94 (1H, dd, J=2.5 Hz, J=8.6 Hz), 7.01 (1H, d, J=2.5 Hz), 7.27-7.50 (2H, m), 7.53 (1H, t, J=15.6 Hz), 7.68-7.81 (2H, m), 7.92-8.03 (1H, m), 12.86 (2H, br); NMR (14) DMSO-d₆) δppm: 0.82 (3H, t, J=7.2 Hz), 1.17-1.40 (2H, m), 1.40-1.61 (2H, m), 2.72-2.90 (2H, m), 5.06 (2H, s), 6.46 (1H, d, J=15.7 Hz). 6.91-7.07 (2H, m), 7.30-7.41 (1H, m), 7.41-7.54 (1H, m), 7.51 (1H, d, J=15.7 Hz), 7.74-7.82 (2H, m), 8.00-8.04 (1H, m); NMR (15) (DMSO-d₆) δppm: 5.08 (2H, s), 6.50 (1H, d, =15.7 Hz), 7.13 (1H, dd, J=2.5 Hz, J=8.7 Hz), 7.27-7.49 (4H, m), 7.71 (1H, d, J=8.7 Hz), 7.76 (1H, d, J=7.0 Hz), 7.99 (1H, d, J=7.0 Hz), 12.85 (1H, br); NMR (16) (DMSO-d₆) δppm: 5.09 (2H, s), 6.61 (1H, d, J=15.6 Hz), 6.98-7.13 (2H, m), 7.30 (1H, t, J=7.1 Hz), 7.44 (1H, t, J=7.1 Hz), 7.63 (1H, dd, J=3.4 Hz, J=15.6 Hz), 7.74-7.90 (2H, m), 7.97 (1H, d, J=7.1 Hz), 12.88 (1H, br); NMR (17) (DMSO-d₆) δppm: 3.89 (3H, s), 5.06 (2H, s), 6.51 (1H, d, J=15.5 Hz), 6.71 (1H, d, J=2.2 Hz, J=8.7 Hz), 6.82 (1H, d, J=2.2 Hz), 7.25-7.50 (2H, m), 7.66 (1H, d, J=8.7 Hz), 7.70 (1H, d, J=15.5 Hz), 7.74-7.81 (1H, m), 7.94-8.03 (1H, m), 12.80 (2H, br); NMR (18) (DMSO-d₆) δppm: 1.34 (3H, t, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz), 5.05 (2H, s), 6.45 (1H, d, J=15.5 Hz), 6.68 (1H, dd, J=2.0 Hz, J=8.7 Hz), 6.77 (1H, d, J=2.0 Hz), 7.26-7.50 (2H, m), 7.66 (1H, d, J=8.7 Hz), 7.72-7.81 (1H, m), 7.79 (1H, d, J=15.5 Hz), 7.91-8.05 (1H, m), 12.77 (2H, br); NMR (19) DMSO-d₆) δppm: 3.89 (3H, s), 5.09 (2H, s), 6.67 (1H, d, J=15.5 Hz), 7.08 (1H, d, J=8.5 Hz), 7.25-7.55 (2H, m), 7.57 (1H, m), 7.7-8.1 (4H, m), 11.68 (1H, br); NMR (20) (DMSO-d₆) δppm: 1.29 (6H, d, J=6.0 Hz), 4.82 (1H, sept, J=6.0 Hz), 5.05 (2H, s), 6.43 (1H, d, J=15.5 Hz), 6.89 (1H, dd, J=2.3 Hz, J=8.7 Hz), 6.78 (1H, d, J=2.3 Hz), 7.31 (1H, t, J=7.0 Hz), 7.45 (1H, t, J=7.0 Hz), 7.66 (1H, d, J=8.7 Hz), 7.78 (1H, d, J=15.5 Hz), 7.80 (1H, d, J=7.0 Hz), 7.99 (1H, d, J=7.0 Hz), 12.76 (1H, br); NMR (21) (DMSO-d₆) δppm: 4.92 (2H, q, J=8.7 Hz), 5.07 (2H, s), 6.48 (1H, d, J=15.5 Hz), 6.81 (1H, dd, J=2.3 Hz, J=8.8 Hz), 6.93 (1H, d, J=2.3 Hz), 7.32 (1H, t, J=7.0 Hz), 7.45 (1H, t, J=7.0 Hz), 7.62-7.79 (3H, m), 7.99 (1H, d, J=7.0 Hz), 12.78 (1H, br); NMR (22) DMSO-d₆) δppm: 5.28 (2H, s), 6.69 (1H, d, J=15.5 Hz), 7.25-7.55 (3H, m), 7.77 (1H, d, J=8 Hz), 7.92 (1H, d, J=15.5 Hz), 7.98 (1H, d, J=7.5 Hz), 8.15-8.45 (2H, m), 12.88 (1H, br); NMR (23) (DMSO-d₆) δppm: 1.03 (3H, t, J=7 Hz), 1.18 (3H, t, J=7 Hz), 3.1-3.5 (4H, m), 4.96 (2H, s), 5.10 (2H, s), 6.63 (1H, d, J=15.5 Hz), 7.10 (1H, d, J=8.5 Hz), 7.25-7.55 (3H, m), 7.7-7.85 (2H, m), 7.86 (1H, d, J=15.5 Hz), 7.98 (1H, d, J=7.5 Hz), 12.66 (1H, br); NMR (24) (DMSO-d₆) δppm: 3.90 (3H, s), 5.18 (2H, s), 6.67 (1H, d, J=15.5 Hz), 7.28-7.36 (2H, m), 7.46 (1H, t, J=7.6 Hz), 7.78 (1H, d, J=7.6 Hz), 7.89 (1H, d, J=15.5 Hz), 7.99 (1H, t, J=7.6 Hz), 8.25 (1H, dd, J=2.3 Hz, J=8.9 Hz) 8.38 (1H, d, J=2.3 Hz); NMR (25) DMSO-d₆) δppm: 2.48 (2H, t, J=7.5 Hz), 3.12 (2H, t, J=7.5 Hz), 5.04 (2H, s), 6.52 (1H, d, J=15.7 Hz), 7.13 (1H, d, J=8.7 Hz), 7.34 (1H, t, J=7.2 Hz), 7.42-7.63 (3H, m), 7.80 (1H, d, J=7.6 Hz), 8.02 (1H, d, J=7.2 Hz), 10.33 (1H, br), 12.98 (1H, br); NMR (26) (DMSO-d₆) δppm: 2.71 (2H, t, J=7.6 Hz), 2.98 (2H, t, J=7.6 Hz), 3.59 (3H, s), 5.13 (2H, s), 6.60-6.75 (1H, m), 7.04-7.08 (1H, m), 7.27-7.38 (1H, m), 7.38-7.51 (1H, m), 7.55-7.78 (1H, m), 7.84-7.99 (4H, m), 9.40 (2H, brs); NMR (27) (DMSO-d₆ +CDCl₃) δppm: 2.66 (2H, t, J=8.8 Hz), 2.84 (3H, s), 2.89-3.06 (5H, m), 5.01 (2H, s), 6.57-6.75 (1H, m), 6.90-7.10 (1H, m), 7.18-7.30 (1H, m), 7.30-7.41 (1H, m), 7.63-7.72 (1H, m), 7.72-7.90 (3H, m), 7.96 (1H, s), 11.50-13.00 (2H, brs); NMR (28) (DMSO-d₆) δppm: 1.00 (3H, t, J=7.0 Hz), 1.07 (3H, t, J=7.0 Hz), 2.68 (2H, t, J=7.4 Hz), 3.01 (2H, t, J=7.4 Hz), 3.15-3.46 (4H, m), 5.06 (2H, s), 6.78 (2H, d, J=15.4 Hz), 6.95-6.99 (1H, m), 7.25-7.30 (1H, m), 7.38-7.43 (1H, m), 7.72-7.85 (5H, m); NMR (29) (DMSO-d₆) δppm: 1.12 (3H, t, J=7.1 Hz), 2.69 (2H, t, J=7.8 Hz), 2.98 (2H, t, J=7.8 Hz), 4.00 (2H, q, J=7.1 Hz), 5.13 (2H, s), 6.61 (1H, d, J=15.4 Hz), 7.04 (1H, d, J=8.8 Hz), 7.30-7.40 (1H, m), 7.55 (1H, m), 7.75 (1H, d, J=7.3 Hz), 7.86 (1H, d, J=15.4 Hz), 7.91-8.10 (3H, m), 12.40-13.30 (2H, m).

Using the suitable starting compounds, the compounds as listed in Tables 50-125 are obtained in the same manner as in Example 3 or 4.

                  TABLE 50                                                         ______________________________________                                          ##STR363##                                                                    ______________________________________                                         Example 56                                                                      ##STR364# R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        -                                                                             R.sup.11b : H                                                                                              R.sup.5 : H                                         -                                                                           M.p. 175-185° C.                                                                    Crystalline form: White powder                                     Solvent for recrystallization: Ethanol                                                            Form: Free NMR (1)                                          Example 57                                                                      ##STR366# R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        -                                                                             R.sup.11b : H                                                                                              R.sup.5 : Isopropyl  (2-position)                   -                                                                           M.p. 190-192° C.                                                                    Crystalline form: Pale brown powder                                Solvent for recrystallization: Ethanol                                                            Form: Free Trans-form                                       ______________________________________                                    

                  TABLE 51                                                         ______________________________________                                         Example 58                                                                      ##STR368##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : H                                      -                                                                           M.p. 202.5-225° C. (decomp.) Crystalline form: White powder NMR         (2)                                                                              Solvent for recrystallization: Ethanol-diethyl ether                                                     Form: 2HCl                                         Example 59                                                                      ##STR370##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : Isopropyl  (2-position)                                              -                                              M.p. 186-190° C. (decomp.)                                                              Crystalline form: Yellow powder                                Solvent for recrystallization: Ethanol-diethyl ether                                                   Form: 2HCl                                             Example 60                                                                      ##STR372##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : H                                       -                                                                           M.p. 202-206° C.(decomp.) Crystalline form: Yellow powder Form:         2HCl                                                                             Solvent for recrystallization: Ethanol-diethyl ether                         ______________________________________                                    

                  TABLE 52                                                         ______________________________________                                         Example 61                                                                      ##STR374##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                          R.sup.5 : Isopropyl (2-position)                        -                                                                           M.p. 114-115° C.                                                                  Crystalline form: Pale yellow powder                                                               Cis-form                                         Solvent for recrystallization: Ethanol-water                                                         Form: Free                                               Example 62                                                                      ##STR376##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                          R.sup.5 : Cl (2-position)                               -                                                                           M.p. 206.5-209° C.                                                                  Crystalline form: White powder                                     Solvent for recrystallization: Ethanol-water                                                         Form: Free                                               Example 63                                                                       R.sup.1 : CH.sub.3 R.sup.4 : H A: --CH.sub.2 -- m: 1                           R.sup.2 : H                                                                     -                                                                             R.sup.11b : H                                                                                          R.sup.5 : H                                             -                                                                           M.p. 138.5-141.5° C.                                                                Crystalline form: White powder                                       Form: Free                                                                   ______________________________________                                    

                  TABLE 53                                                         ______________________________________                                         Example 64                                                                      ##STR379##     R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : H                                      -                                                                           M.p. 221-222.5° C.                                                                   Crystalline form: Pale yellow powder                                Form: Free                                                                   Example 65                                                                      ##STR381##     R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : Cl  (2-position)                       -                                                                           M.p. 181-183° C.                                                                     Crystalline form: White powder                                    Solvent for recrystallization: Ethanol-diethyl ether                                                   Form: Free                                             Example 66                                                                      ##STR383##     R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3  (2-position)                                               -                                             M.p. 261-262° C.                                                                     Crystalline form: Yellow powder                                   Solvent for recrystallization: Ethanol                                                                 Form: 2HCl                                             ______________________________________                                    

                  TABLE 54                                                         ______________________________________                                         Example 67                                                                      ##STR385##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : C.sub.2 H.sub.5  (2-position)                                        -                                             M.p. 227-229° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol                                                                 Form: 2HCl                                             Example 68                                                                      ##STR387##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : F  (2-position)                        -                                                                           M.p. 226-227° C.                                                                     Crystalline form: Brown powder                                    Solvent for recrystallization: Ethanol                                                                 Form: 2HCl                                             Example 69                                                                      ##STR389##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3  (2-position)                                               -                                             Solvent for recrystallization: Ethanol Crystalline form: Pale yellow           powder                                                                           Form: 3HCl   NMR (3)                                                         ______________________________________                                    

                  TABLE 55                                                         ______________________________________                                         Example 70                                                                      ##STR391##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : C.sub.2 H.sub.5  (2-position)                                        -                                             M.p. 157-160° C.                                                                    Crystalline form: Pale yellow powder                               Solvent for recrystallization: Ethanol                                                            Form: 3HCl                                                  Example 71                                                                      ##STR393##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : F  (2-position)                        -                                                                           Solvent for recrystallization: Ethanol                                                           Crystalline form: Brown powder                                 Form: 3HCl NMR (4)                                                           Example 72                                                                      ##STR395##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : n-Propyl  (2-position)                                               -                                             Crystalline form: Yellow powder                                                                 Form: 3HCl NMR (5)                                            ______________________________________                                    

                  TABLE 56                                                         ______________________________________                                         Example 73                                                                      ##STR397##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : Cl  (2-position)                        -                                                                           M.p. 200° C.                                                                       Crystalline form: Yellow powder                                     Solvent for recrystallization: Ethanol-water                                                          Form: 2HCl                                              Example 74                                                                      ##STR399##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : C.sub.2 H.sub.5  (2-position)                                        -                                              M.p. 115-118° C.                                                                   Crystalline form: Pale beige powder                                 Solvent for recrystallization: Ethanol                                                                Form: 2HCl                                              Example 75                                                                      ##STR401##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : Isopropyl  (2-position)                                              -                                              M.p. 188-191° C.                                                                   Crystalline form: White powder                                                                    Form: 2HCl                                       Solvent for recrystallization: Ethanol-water-diethyl ether                     ______________________________________                                    

                  TABLE 57                                                         ______________________________________                                         Example 76                                                                      ##STR403##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : n-Propyl  (2-position)                  -                                                                           Crystalline form: Pale yellow powder                                                              Form: 3HCl  NMR (6)                                         Example 77                                                                      ##STR405##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : C.sub.2 H.sub.5  (2-position)                                        -                                              M.p. 228-230° C.                                                                    Crystalline form: Pale yellow powder                               Solvent for recrystallization: Ethanol                                                            Form: 2HCl                                                  Example 78                                                                      ##STR407##   R                                                                             .sup.4 : H m: 1                                                      -                                                                             #STR408##                                                                       -                                                                             R.sup.11b : H                                                                            #STR409##                                                             -                                                                           M.p. 203-205° C.                                                                  Crystalline form White powder                                                                    Form: 3HCl                                         Solvent for recrystallization: Methanol-diethyl ether                          ______________________________________                                    

                  TABLE 58                                                         ______________________________________                                         Example 79                                                                      ##STR410##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : n-Propyl  (2-position)                                               -                                             M.p. 202-204° C.                                                                        Crystalline form: White powder                                 Solvent for recrystallization: Ethyl acetate-n-hexane                                                    Form: 3HCl                                           Example 80                                                                      ##STR412##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : n-Propyl  (2-position)                                               -                                             Crystalline form: Yellow powder                                                                  Form: 2HCl  NMR (9)                                          Example 81                                                                      ##STR414##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : Cl  (2-position)                       -                                                                           M.p. 171° C.                                                                     Crystalline form: Pale yellow powder                                                                Form: 2HCl                                       Solvent for recrystallization: Ethanol-water                                   ______________________________________                                    

                  TABLE 59                                                         ______________________________________                                         Example 82                                                                      ##STR416##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3  (2- and  6-positions)        -                                                                           M.p. 233-235° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol                                                                Form: Free                                              Example 83                                                                      ##STR418##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3  (2- and  6-positions)        -                                                                           M.p. 206-210° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol                                                                Form: Free                                              Example 84                                                                      ##STR420##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : F  (2-position)                        -                                                                           M.p. 205-208° C.                                                                     Crystalline form: White powder                                    Solvent for recrystallization: Ethanol-water                                                          Form: 2HCl                                              ______________________________________                                    

                  TABLE 60                                                         ______________________________________                                         Example 85                                                                      ##STR422##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : F  (2-position)                        -                                                                           M.p. 173-175° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-water-diethyl ether                                                Form: 2HCl                                          Example 86                                                                      ##STR424##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                                      R.sup.5 : C.sub.2 H.sub.5 OOC(CH.sub.2).sub.2 -- (2-position)                    -                                                                   R.sup.11b : H                                                                                                 #STR425##                                        -                                                                           M.p. 152.4-156.3° C.                                                                 Crystalline form: White powder                                    Solvent for recrystallization: Ethanol-water-diethyl ether                                                Form: 3HCl                                          Example 87                                                                      ##STR426##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : F  (2-position)                        -                                                                           M.p. 150-153° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Dichloromethane-diethyl ether                                              Form: Free                                          ______________________________________                                    

                  TABLE 61                                                         ______________________________________                                         Example 88                                                                      ##STR428##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             Crystalline form: Pale yellow powder                                                                     Form: 2HCl                                             Solvent for recrystallization: Ethanol-water NMR (11)                        Example 89                                                                      ##STR430##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 203-206° C.                                                                        Crystalline form: Pale yellow powder                           Solvent for recrystallization: Ethanol-water-diethyl ether                                               Form: 2HCl                                           Example 90                                                                      ##STR432##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : n-Butyl  (2-position)                  -                                                                           M.p. 161.7-165° C.                                                                      Crystalline form: Pale yellow powder                           Solvent for recrystallization: Ethanol-water-diethyl ether                                               Form: 3HCl                                           ______________________________________                                    

                  TABLE 62                                                         ______________________________________                                         Example 91                                                                      ##STR434##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : n-Butyl  (2-position)                  -                                                                           M.p. 153-155.5° C.                                                                   Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-water-diethyl ether                                               Form: 3HCl                                           Example 92                                                                      ##STR436##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CF.sub.3  (2-position)                                               -                                             M.p. 185-187° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Isopropyl alcohol-water                                                   Form: 2HCl                                           Example 93                                                                      ##STR438##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CF.sub.3  (2-position)                                               -                                             M.p. 175-178° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           ______________________________________                                    

                  TABLE 63                                                         ______________________________________                                         Example 94                                                                      ##STR440##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                                      R.sup.5 : CH.sub.3 COO(CH.sub.2).sub.4 -- (2-position)                           -                                                                   R.sup.11b : H                                                                                                 #STR441##                                        -                                                                           M.p. 151-154° C.                                                                     Crystalline form: White powder                                    Solvent for recrystallization: Ethanol-water-diethyl ether                                               Form: 3HCl                                           Example 95                                                                      ##STR442##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : n-Butyl  (2-position)                  -                                                                           M.p. 167-168° C.                                                                     Crystalline form: White powder                                    Solvent for recrystallization: Ethanol-water                                                             Form: 3HCl                                           Example 96                                                                      ##STR444##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : n-Butyl  (2-position)                  -                                                                           M.p. 135-137° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-water-diethyl ether                                               Form: 3HCl                                           ______________________________________                                    

                  TABLE 64                                                         ______________________________________                                         Example 97                                                                      ##STR446##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 183.5-186° C.                                                                   Crystalline form: Yellow powder                                   Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           Example 98                                                                      ##STR448##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 174-176° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           Example 99                                                                      ##STR450##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 153-154° C.                                                                     Crystalline form: Yellow powder                                   Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           ______________________________________                                    

                  TABLE 65                                                         ______________________________________                                         Example 100                                                                     ##STR452##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 177.5-179.5° C.                                                                 Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-water                                                             Form: 3HCl                                           Example 101                                                                     ##STR454##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 165-168° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-water-diethyl ether                                               Form: 3HCl                                           Example 102                                                                     ##STR456##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 161.5-164° C.                                                                   Crystalline form: Yellow powder                                   Solvent for recrystallization: Ethanol-water                                                             Form: HCl                                            ______________________________________                                    

                  TABLE 66                                                         ______________________________________                                         Example 103                                                                     ##STR458##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                  R.sup.5 : CH.sub.3 O  (2-  position)                                           -                                            M.p. 181-183° C.                                                                     Crystalline form: White powder                                    Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           Example 104                                                                     ##STR460##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 :  C.sub.2 H.sub.5 O--  (2-positi                                    on)                                                -                                                                           M.p. 174-177° C.                                                                   Crystalline form: Pale yellow powder                                                               Form: 2HCl                                      Solvent for recrystallization: Ethanol-water-isopropyl alcohol-diethyl         ether                                                                            Example 105                                                                   # RTR462##                                                                      .sup.4 : H A: --CH.sub.2 -- m: 1                                                -                                                                             R.sup.11b : H                                                                                                 R.sup.5 :  C.sub.2 H.sub.5 O--  (2-positi                                    on)                                                -                                                                           M.p. 194-196° C.                                                                   Crystalline form: Yellow powder                                                                    Form: 2HCl                                      Solvent for recrystallization: Ethanol-water-isopropyl alcohol-diethyl         ether                                                                          ______________________________________                                    

                  TABLE 67                                                         ______________________________________                                         Example 106                                                                     ##STR464##     R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 200-203° C.                                                                       Crystalline form: Pale yellow powder                            Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           Example 107                                                                     ##STR466##     R                                                                             .sup.4 : H A: --CH(CH.sub.3)-- m: 1                                -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 169-170° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol                                                                   Form: 2HCl                                           Example 108                                                                     ##STR468##     R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 181-189° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-water                                                        Form: 3HCl                                                                               NMR (12)                                        ______________________________________                                    

                  TABLE 68                                                         ______________________________________                                         Example 109                                                                     ##STR470##     R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 158-160° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-water                                                             Form: 3HCl                                           Example 110                                                                     ##STR472##     R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 176.5-181.5° C.                                                                 Crystalline form: Yellow powder                                   Solvent for recrystallization: Ethanol-water                                                        Form: 3HCl                                                                               NMR (13)                                        Example 111                                                                     ##STR474##     R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 141-142° C.                                                                     Crystalline form: White powder                                    Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           ______________________________________                                    

                  TABLE 69                                                         ______________________________________                                         Example 112                                                                     ##STR476##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 131.5-133° C.                                                                   Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           Example 113                                                                     ##STR478##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             Crystalline form: Pale yellow amorphous                                                             Form: Free                                                                               NMR (14)                                        Example 114                                                                     ##STR480##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 140-142° C.                                                                     Form: Methanesulfonate                                            Solvent for recrystallization: Ethanol-diisopropyl ether                         Crystalline form: Pale yellow powder                                         ______________________________________                                    

                  TABLE 70                                                         ______________________________________                                         Example 115                                                                     ##STR482##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : CH.sub.3 O  (2-position)                                             -                                              M.p. 168.5-169° C.                                                                   Crystalline form: White powder                                    Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           Example 116                                                                     ##STR484##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : CH.sub.3 O  (2-position)                                             -                                              M.p. 128.2-131.5° C.                                                                Crystalline form: Yellow powder                                                                  Form: Free                                       Solvent for recrystallization: Ethanol-diethyl ether-dichloromethane             Example 117                                                                   # RTR486##                                                                      .sup.4 : H A: --CH.sub.2 -- m: 1                                                -                                                                             R.sup.11b : H                                                                                                R.sup.5 : CH.sub.3 O  (2-position)                                             -                                              M.p. 144-146° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol                                                             Form: Methanesulfonate                                     ______________________________________                                    

                  TABLE 71                                                         ______________________________________                                         Example 118                                                                     ##STR488##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : C.sub.2 H.sub.5 O--  (2-position                                   )                                                   -                                                                           M.p. 190-192° C.                                                                     Crystalline form: Yellow powder                                   Form: Methanesulfonate                                                           Solvent for recrystallization: Ethanol-isopropyl alcohol-diethyl             ether-water                                                                      Example 119                                                                   # RTR490##                                                                      .sup.4 : H A: --CH.sub.2 -- m: 1                                                -                                                                                      R.sup.5 : CH.sub.3 OOC(CH.sub.2).sub.2 -- (2-position)                           -                                                                   R.sup.11b : H                                                                                                #STR491##                                         -                                                                           M.p. 110-111° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol                                                                   Form: Free                                           Example 120                                                                     ##STR492##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                                      R.sup.5 : (CH.sub.3).sub.2 NOC(CH.sub.2).sub.2 -- (2-position)         -                                                                             R.sup.11b : H                                                                                                #STR493##                                         -                                                                           M.p. 162.5-164° C.                                                                   Crystalline form: Yellow powder                                   Solvent for recrystallization: Ethanol-water                                                             Form: HCl                                            ______________________________________                                    

                  TABLE 72                                                         ______________________________________                                         Example 121                                                                     ##STR494##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : CH.sub.3 O  (2-position)                                             -                                              M.p. 205-207.5° C.                                                                   Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           Example 122                                                                     ##STR496##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                                      R.sup.5 : (C.sub.2 H.sub.5).sub.2 NOCCH.sub.2 O-- (2-position)         -                                                                             R.sup.11b : H                                                                                                #STR497##                                         -                                                                           M.p. 167-169° C.                                                                     Crystalline form: White powder                                    Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           Example 123                                                                     ##STR498##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                R.sup.5 : CH.sub.3 O--  (2-position)                                           -                                              M.p. 190.5-192.5° C.                                                                Crystalline form: Yellow powder                                                                  Form: Free                                       Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether           ______________________________________                                    

                                      TABLE 73                                     __________________________________________________________________________     Example 124                                                                     ##STR500##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                             R.sup.5 : CH.sub.3 O-- (2-position)                  -                                                                           M.p. 148.2-149° C.                                                                 Crystalline form: Pale yellow powder                                                             Form: Free                                        Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether           Example 125                                                                     ##STR502##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                             R.sup.5 : CH.sub.3 O-- (2-position)                  -                                                                           M.p. 211-211.5° C.                                                                 Crystalline form: Pale yellow powder                                Solvent for recrystallization: Ethanol-dichloromethane                                                 Form: Free                                             Example 126                                                                     ##STR504##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                             R.sup.5 : CH.sub.3 O-- (2-position)                  -                                                                           M.p. 204-206° C.                                                                   Crystalline form: White needles                                     Solvent for recrystallization: Ethanol-dichloromethane                                                 Form: Free                                             __________________________________________________________________________

                  TABLE 74                                                         ______________________________________                                         Example 127                                                                     ##STR506##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 O-- (2-position)                    -                                                                           M.p. 168-170.4° C.                                                                  Crystalline form: White needles                                                                   Form: Free                                      Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether             Example 128                                                                   # RTR508##                                                                      .sup.4 : H A: --CH.sub.2 -- m: 1                                                -                                                                             R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 O-- (2-position)                    -                                                                           M.p. 175.8-177.2° C.                                                                    Crystalline form: White powder                                 Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           Example 129                                                                     ##STR510##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                           R.sup.5 : C.sub.2 H.sub.5 (2-position)                                         -                                                   M.p. 130-132.5° C.                                                                      Form: Dimethanesulfonate                                       Solvent for recrystallization: Ethanol-diethyl ether                             Crystalline form: Yellow powder                                              ______________________________________                                    

                  TABLE 75                                                         ______________________________________                                         Example 130                                                                     ##STR512##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                             R.sup.5 : C.sub.2 H.sub.5 O--  (2-position)                                    -                                                 M.p. 225-226° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Dichloromethane-ethanol                                                   Form: Free                                           Example 131                                                                     ##STR514##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                             R.sup.5 : CH.sub.3 O (2-position)                    -                                                                           M.p. 222-223° C.                                                                     Crystalline form: White powder                                    Solvent for recrystallization: Methanol-dichloromethane                                                  Form: Free                                           Example 132                                                                     ##STR516##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                             R.sup.5 : C.sub.2 H.sub.5 O--  (2-position)                                    -                                                 M.p. 122.5-125° C.                                                                   Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           ______________________________________                                    

                  TABLE 76                                                         ______________________________________                                         Example 133                                                                     ##STR518##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 162-163° C.                                                                     Crystalline form: White powder                                    Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           Example 134                                                                     ##STR520##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 177.2-178° C.                                                                   Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           Example 135                                                                     ##STR522##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : C.sub.2 H.sub.5  (2-position)                                        -                                             M.p. 140-155° C. (decomp.) Crystalline form: White powder NMR (27)       Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether           Form: Free                                                                    ______________________________________                                    

                  TABLE 77                                                         ______________________________________                                         Example 136                                                                     ##STR524##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 171-172.2° C.                                                                 Crystalline form: White needles                                                                   Form: Free                                       Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether             Example 137                                                                   # RTR526##                                                                      .sup.4 : H A: --CH.sub.2 -- m: 1                                                -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 232.5-233° C.                                                                   Crystalline form: Yellow powder                                   Solvent for recrystallization: Dichloromethane-ethanol                                                   Form: Free                                           Example 138                                                                     ##STR528##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             Crystalline form: Pale yellow amorphous                                                               NMR (28)                                                  Form: 3HCl                                                                   ______________________________________                                    

                  TABLE 78                                                         ______________________________________                                         Example 139                                                                     ##STR530##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (2-position)                     -                                                                           M.p. 192-194° C.                                                                     Crystalline form: Yellow powder                                   Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           Example 140                                                                     ##STR532##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (2-position)                     -                                                                           M.p. 201-204 ° C.                                                                    Crystalline form: Yellow powder                                   Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           Example 141                                                                     ##STR534##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (2-position)                     -                                                                           M.p. 172-175° C.                                                                     Crystalline form: Yellow powder                                   Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           ______________________________________                                    

                  TABLE 79                                                         ______________________________________                                         Example 142                                                                     ##STR536##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 146.5-148° C.                                                                   Crystalline form: Yellow powder                                   Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           Example 143                                                                     ##STR538##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 114-117° C.                                                                     Crystalline form: Pale yellow powder                              Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           Example 144                                                                     ##STR540##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                             R.sup.11b : H                                                                                                 R.sup.5 : CH.sub.3 O  (2-position)                                             -                                             M.p. 176-181° C.                                                                  Crystalline form: Pale yellow powder                                                               Form: 2HCl                                       Solvent for recrystallization: Ethanol-water-diethyl ether                                               NMR (29)                                             ______________________________________                                    

                                      TABLE 80                                     __________________________________________________________________________     Example 145                                                                     ##STR542 R                                                                             .sup.4 : --CH.sub.2 OCOC(CH.sub.3).sub.3 A: --CH.sub.2 -- m: 1          R.sup.11b : H                                                                                  R.sup.5 : CH.sub.3 O (2-position)                               -                                                                           M.p. 106.5-108.2° C.                                                               Crystalline form: Pale yellow powder                                Solvent for recrystallization: Ethanol-diethyl ether-n-hexane                                               Form: Free                                        Example 146                                                                     ##STR544 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (2-position)                     -                                                                           M.p. 189-190° C.                                                                 Crystalline form: White powder                                        Solvent for recrystallization: Ethanol-dichloromethane                                                     Form: Free                                         Example 147                                                                     ##STR546 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (2-position)                     -                                                                           M.p. 151-153° C.                                                                    Crystalline form: White powder                                     Solvent for recrystallization: Ethyl acetate-diethyl ether                                                 Form: Free                                         __________________________________________________________________________

                  TABLE 81                                                         ______________________________________                                         Example 148                                                                     ##STR548##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                         R.sup.5 : CH.sub.3 O (2-position)                        -                                                                           M.p. 145-147° C.                                                                    Crystalline form: White powder                                                                   Form: Free                                       Solvent for recrystallization: Ethyl acetate-chloroform                          Example 149                                                                   # RTR550##                                                                      .sup.4 : H A: --CH.sub.2 -- m: 1                                               R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 O (2-position)                      -                                                                           M.p. 189-190.5° C.                                                                    Crystalline form: Pale yellow powder                             Solvent for recrystallization: Ethyl acetate-chloroform                                                  Form: Free                                           Example 150                                                                     ##STR552##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                          R.sup.5 : Isopropyl (2-position)                        -                                                                           M.p. 196-199° C. (decomp.)                                                               Crystalline form: Pale yellow powder                          Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           ______________________________________                                    

                                      TABLE 82                                     __________________________________________________________________________     Example 151                                                                     ##STR554##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                       R.sup.5 : C.sub.2 H.sub.5 O-- (2-position)                                     -                                                       M.p. 155-158° C. (decomp.)                                                           Crystalline form: Yellow powder                                                                 Form: Free                                       Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether           Example 152                                                                     ##STR556##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                         R.sup.5 : CH.sub.3 O (2-position)                        -                                                                           M.p. 162-164° C.                                                                      Crystalline form: White powder                                   Solvent for recrystallization: Ethyl acetate-diethyl ether                                                 Form: Free                                         Example 153                                                                     ##STR558##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                       R.sup.5 : n-Propyl (2-position)                            -                                                                           M.p. 137-139° C. (decomp.)                                                                 Crystalline form: Pale yellow powder                        Solvent for recrystallization: Ethanol-dichloromethane                                                     Form: Free                                         __________________________________________________________________________

                                      TABLE 83                                     __________________________________________________________________________     Example 154                                                                     ##STR560##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                              R.sup.5 : CH.sub.3 O   (2-position)                                            -                                                M.p. 158-159° C.                                                                    Crystalline form: White powder                                                                  Form: Free                                        Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether           Example 155                                                                     ##STR562##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                             R.sup.5 : CH.sub.3 O (2-position)                    -                                                                           M.p. 154-154.5 C.                                                                          Crystalline form: White powder                                                                  Form: Free                                        Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether           Example 156                                                                     ##STR564##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : --CH.sub.3                                                                                    R.sup.5 : CH.sub.3 O (2-position)                    -                                                                           M.p. 180-181.5° C.                                                                  Crystalline form: Dark yellow powder                                                              Form: HCl                                       Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether           __________________________________________________________________________

                                      TABLE 84                                     __________________________________________________________________________     Example 157                                                                     ##STR566## R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      R.sup.11b : H                                                                                       R.sup.5 : C.sub.2 H.sub.5 (2-position)                     -                                                                           M.p. 165-175° C. (decomp.)                                                           Crystalline form: Yellow powder                                                                NMR (30)                                          Solvent for recrystallization: Dichloromethane-ethanol-diethyl ether                                        Form: Free                                        Example 158                                                                     ##STR568## R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      R.sup.11b : H                                                                                       R.sup.5 : CH.sub.3 O (2-position)                          -                                                                           M.p. 125-128° C.                                                                   Crystalline form: Yellow powder                                                                Form: Free                                          Solvent for recrystallization: Ethanol-dichloromethane                         Example 159                                                                     ##STR570## R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      R.sup.11b : H                                                                                       R.sup.5 : CH.sub.3 (2-position)                            -                                                                           M.p. 195-195.5° C.                                                                 Crystalline form: Pale yellow powder                                                             Form: Free                                        Solvent for recrystallization: Ethanol-dichloromethane                         __________________________________________________________________________

                                      TABLE 85                                     __________________________________________________________________________     Example 160                                                                     ##STR572# R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                       R.sup.11b : H                                                                                        R.sup.5 : CF.sub.3 (2-position)                           -                                                                           M.p. 188-189° C.                                                                  Crystalline form: Pale yellow powder                                                               Form: Free                                       Solvent for recrystallization: Ethanol-dichloromethane                         Example 161                                                                     ##STR574# R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                       R.sup.11b : H                                                                                        R.sup.5 : F (2-position)                                  -                                                                           M.p. 197-200 ° C.                                                                 Crystalline form: Pale yellow powder                                                               Form: Free                                       Solvent for recrystallization: Ethanol-dichloromethane                         Example 162                                                                     ##STR576# R                                                                             .sup.4 : H m: 1                                                                              RSTR577##                                                                    .sup.11b : H                                                -                                                                                                   #STR578##                                                 -                                                                           M.p. 138-141° C.                                                                  Crystalline form: White powder                                                                 Form: Free                                           __________________________________________________________________________

                                      TABLE 86                                     __________________________________________________________________________     Example 163                                                                     ##STR579## R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      R.sup.11b : H                                                                                         R.sup.5 : CH.sub.3 O (2-position)                        -                                                                           M.p. 155.5-158° C.                                                                 Crystalline form: Pale brown powder                                                              Form: Free                                        Solvent for recrystallization: Ethanol-dichloromethane                         Example 164                                                                     ##STR581## R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 (2-position)                        -                                                                           M.p. 163-166° C.                                                                   Crystalline form: Brown powder                                                                 Form: Free                                          Solvent for recrystallization: Dichloromethane-ethanol-diethyl ether           Example 165                                                                     ##STR583## R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      R.sup.11b : H                                                                                           R.sup.5 : n-Butyl (2-position)                         -                                                                           M.p. 161-163.4° C.                                                                 Crystalline form: Yellow powder                                                                  Form: 2HCl                                        Solvent for recrystallization: Ethanol-dichloromethane-water                   __________________________________________________________________________

                                      TABLE 87                                     __________________________________________________________________________     Example 166                                                                     ##STR585# R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                       R.sup.11b : H                                                                                          R.sup.5 : n-Butyl (2-position)                          -                                                                           M.p. 137-139° C.                                                                  Crystalline form: Pale brown powder                                                                Form: Free                                       Solvent for recrystallization: Ethanol-dichloromethane-water                   Example 167                                                                     ##STR587# R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                       R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 (2-position)                       -                                                                           M.p. 215-217° C.                                                                  Crystalline form: Pale yellow powder                                                               Form: Free                                       Solvent for recrystallization: Ethanol-dichloromethane                         Example 168                                                                     ##STR589# R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                       R.sup.11b : H                                                                                            R.sup.5 : n-Heptyl (2-position)                       -                                                                           M.p. 146.5-149° C.                                                                  Crystalline form: Pale yellow powder                               Solvent for recrystallization: Ethanol-dichloromethane-water                                                 Form: 2HCl                                       __________________________________________________________________________

                                      TABLE 88                                     __________________________________________________________________________     Example 169                                                                     ##STR591# R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                       R.sup.11b : H                                                                                        R.sup.5 : n-Heptyl (2-position)                           -                                                                           M.p. 152-153.5° C.                                                                  Crystalline form: White powder                                     Solvent for recrystallization: Ethanol-dichloromethane-water                                               Form: Free                                         Example 170                                                                     ##STR593# R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                       R.sup.11b : H                                                                                        R.sup.5 : n-Heptyl (2-position)                           -                                                                           M.p. 166.5-169.3° C.                                                                Crystalline form: Yellow powder                                    Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           Example 171                                                                     ##STR595# R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                       R.sup.11b : H                                                                                          R.sup.5 : n-Heptyl (2-position)                         -                                                                           M.p. 155-165° C.                                                                  Crystalline form: Pale yellow powder                                                             Form: 2HCl                                         Solvent for recrystallization: Ethanol-dichloromethane-water                                               NMR (31)                                           __________________________________________________________________________

                                      TABLE 89                                     __________________________________________________________________________     Example 172                                                                     ##STR597# R                                                                             .sup.4 : H A: --(CH.sub.2).sub.3 -- m: 1                               R.sup.11b : H                                                                                        R.sup.5 : CH.sub.3 O (2-position)                         -                                                                           M.p. 219-220° C.                                                                  Crystalline form: Dark yellow powder                                                                Form: Free                                      Solvent for recrystallization: Ethanol-dichloromethane                         Example 173                                                                     ##STR599# R                                                                             .sup.4 : H A: --(CH.sub.2).sub.3 -- m: 1                               R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (2-position)                     -                                                                           M.p. 177-185° C.                                                                  Crystalline form: Dark yellow powder                                                                Form: 3HCl                                      Solvent for recrystallization: Ethanol-dichloromethane-water                                                  NMR (32)                                        __________________________________________________________________________

                                      TABLE 90                                     __________________________________________________________________________     Example 175                                                                     ##STR601 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                            R.sup.5 : C.sub.2 H.sub.5 O (2-position)                                       -                                                  M.p. 182-184° C.                                                                 Crystalline form: Pale yellow powder                                                                 Form: 2HCl                                      Solvent for recrystallization: Ethanol-water-diethyl ether                     Example 176                                                                     ##STR603 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                               R.sup.5 : CH.sub.3 (2-position)                    -                                                                           M.p. 265-270° C.                                                                 Crystalline form: Pale yellow powder                                                                 Form: 2HCl                                      Solvent for recrystallization: Ethanol-water-diethyl ether                                                    NMR (33)                                        Example 177                                                                     ##STR605 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                            R.sup.5 : Isopropyl (2-position)                      -                                                                           M.p. 203-207° C.                                                                 Crystalline form: Pale yellow powder                                                                 Form: 2HCl                                      Solvent for recrystallization: Ethanol-water-diethyl ether                     __________________________________________________________________________

                                      TABLE 91                                     __________________________________________________________________________     Example 178                                                                     ##STR607 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                         -                                                                                    R.sup.5 : CH.sub.3 (2- and 6-positions)                                 R.sup.11b : H                                                                      #STR608##                                                                   -                                                                           M.p. 234-238° C.                                                                 Crystalline form: Pale yellow powder                                                               Form: 2HCl                                        Solvent for recrystallization: Ethanol-water-diethyl ether                     Example 179                                                                     ##STR609 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                           R.sup.5 : F (2-position)                            M.p. 214-217° C.                                                                 Crystalline form: Pale yellow powder                                                               Form: 2HCl                                        Solvent for recrystallization: Ethanol-water                                   Example 180                                                                     ##STR611 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                           R.sup.5 : C.sub.2 H.sub.5 (2-position)              M.p. 188-190° C.                                                                 Crystalline form: Pale yellow powder                                                               Form: 2HCl                                        Solvent for recrystallization: Ethanol-water                                   __________________________________________________________________________

                                      TABLE 92                                     __________________________________________________________________________     Example 181                                                                     ##STR613 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                           R.sup.5 : n-Propyl (2-position)                     M.p. 164-167° C.                                                                 Crystalline form: Yellow powder                                                                  Form: 2HCl                                          Solvent for recrystallization: Ethanol-water                                   Example 182                                                                     ##STR615 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 O (3-position)                   M.p. 165-168° C.                                                                 Crystalline form: Pale yellow powder                                                               Form: 2HCl                                        Solvent for recrystallization: Ethanol-water                                                            NMR (56)                                              Example 183                                                                     ##STR617 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                         -                                                                                    R.sup.5 : CH.sub.3 O (2-position)                                       R.sup.11b : H                                                                      #STR618##                                                                   -                                                                           M.p. 143-145° C.                                                                 Crystalline form: Pale yellow powder                                                               Form: Free                                        Solvent for recrystallization: Ethanol-dichloromethane                         __________________________________________________________________________

                  TABLE 93                                                         ______________________________________                                         Example 184                                                                     ##STR619## R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      R.sup.11b : H                                                                                                 R.sup.5 : H                                      -                                                                           M.p. 215-218.5° C. (decomp.)                                                              Crystalline form: White powder                               Solvent for recrystallization: Ethanol-water-diethyl ether                                               Form: 2HCl                                           Example 185                                                                     ##STR621## R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      R.sup.11b : H                                                                                                 R.sup.5 : CF.sub.3   (2-position)                                              -                                             M.p. 101-106° C.                                                                   Crystalline form: White powder                                                                    Form: 2HCl                                       Solvent for recrystallization: Diethyl ether-ethanol-water                                               NMR (34)                                             Example 186                                                                     ##STR623## R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                       -                                                                                    R.sup.5 : CH.sub.3 O (2-position)                                       R.sup.11b : H                                                                        #STR624##                                                                 -                                                                           M.p. 179-183° C.                                                                   Crystalline form: White powder                                                                    Form: 2HCl                                       Solvent for recrystallization: Ethanol-water-diethyl ether                     ______________________________________                                    

                                      TABLE 94                                     __________________________________________________________________________     Example 187                                                                     ##STR625 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                         -                                                                                    R.sup.5 : C.sub.2 H.sub.5 CH(CH.sub.3)-- (2-position)                   R.sup.11b : H                                                                      #STR626##                                                                   -                                                                           M.p. 129-131° C.                                                                        Crystalline form: Pale yellow powder                           Solvent for recrystallization: Isopropyl alcohol-water                                                    Form: Dioxalate                                     Example 188                                                                     ##STR627 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                           R.sup.5 : C.sub.2 H.sub.5 (3-position)                                         -                                                   M.p. 163-165° C.                                                                 Crystalline form: Pale yellow powder                                                               Form: 2HCl                                        Solvent for recrystallization: Water-ethanol-dichloromethane                   Example 189                                                                     ##STR629 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 (CH.sub.2).sub.4 --                                       (2-position)                                             -                                                                           M.p. 161-162° C.                                                                 Crystalline form: White powder                                                                   Form: 2HCl                                          Solvent for recrystallization: Isopropyl alcohol-water                         __________________________________________________________________________

                                      TABLE 95                                     __________________________________________________________________________      ##STR631##                                                                    __________________________________________________________________________     Example 190                                                                     ##STR632 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 O (4-position)                      -                                                                           M.p. 166-168° C.                                                                 Crystalline form: Yellow powder                                                                  Form: 2HCl                                          Solvent for recrystallization: Water-ethanol-dichloromethane                   __________________________________________________________________________

                                      TABLE 96                                     __________________________________________________________________________      ##STR634##                                                                    __________________________________________________________________________     Example 191                                                                     ##STR635 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                        R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 O (2-position)                      -                                                                           M.p. 175-177° C.                                                                 Crystalline form: White powder                                                                   Form: 2HCl                                          Solvent for recrystallization: Ethanol-water-diethyl ether                     Example 192                                                                     ##STR637 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                         -                                                                                    R.sup.5 : CH.sub.3 (2- and 3-positions)                                 R.sup.11b : H                                                                      #STR638##                                                                   -                                                                           M.p. 158-162° C.                                                                 Crystalline form: Pale yellow powder                                                             Form: Succinate                                     Solvent for recrystallization: Ethanol-diisopropyl ether                       Example 193                                                                     ##STR639 R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                         -                                                                                    R.sup.5 : CH.sub.3 (2- and 3-positions)                                 R.sup.11b : H                                                                      #STR640##                                                                   -                                                                           M.p. 126-128.5° C.                                                               Crystalline form: Yellow powder                                                                  Form: Succinate                                     Solvent for recrystallization: Ethanol-diethyl ether                           __________________________________________________________________________

                  TABLE 97                                                         ______________________________________                                         Example 194                                                                     ##STR641## R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      R.sup.11b : H                                                                                          R.sup.5 : CF.sub.3 (2-position)                         -                                                                           M.p. 166-171° C.                                                                   Crystalline form: Pale yellow powder                                                               Form: HCl                                       Solvent for recrystallization: Isopropyl alcohol-ethanol                                                  NMR (35)                                            Example 195                                                                     ##STR643## R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      R.sup.11b : H                                                                                          R.sup.5 : CH.sub.3 O (3-position)                       -                                                                           M.p. 175-178° C.                                                                   Crystalline form: Yellow powder                                                                    Form: Free                                      Solvent for recrystallization: Methanol                                          Example 196                                                                   # RTR645##                                                                      .sup.4 : H A: --CH.sub.2 -- m: 1                                               R.sup.11b : H                                                                                          R.sup.5 : CH.sub.3 O (3-position)                       -                                                                           M.p. 240-245° C.                                                                   Crystalline form: Pale yellow powder                                                               Form: HCl                                       Solvent for recrystallization: Ethanol-water                                   ______________________________________                                    

                                      TABLE 98                                     __________________________________________________________________________     Example 197                                                                     ##STR647##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3   (3-position)                      -                                                                           M.p. 212--215° C.                                                                   Crystalline form: White powder                                                                 Form: 2HCl                                         Solvent for recrystallization: Ethanol-water                                   Example 198                                                                     ##STR649##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                      -                                                                                       R.sup.5 : --(CH.sub.2).sub.4 -- (combined at 2- and 3-position                 s)                                                                   R.sup.11b : H                                                                      #STR650##                                                                   -                                                                           M.p. 180-190° C.                                                                    Crystalline form: Yellow powder                                                                Form: 2HCl                                         Solvent for recrystallization: Ethanol-diethyl ether                                                       NMR (36)                                           Example 199                                                                     ##STR651##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                     R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 (3-   and 5-  positions)         M.p. 210-216° C.                                                                    Crystalline form: White powder                                                                 Form: 2HCl                                         Solvent for recrystallization: Ethanol-water-diethyl ether                                                 NMR (37)                                           __________________________________________________________________________

                                      TABLE 99                                     __________________________________________________________________________     Example 200                                                                     ##STR653##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                           R.sup.5 : Isopropyl (3-position)                       -                                                                           M.p. 177.5-180.5° C.                                                                   Crystalline form: Pale yellow powder.                           Solvent for recrystallization: Ethanol-water                                                              Form: 2HCl                                          Example 201                                                                     ##STR655##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                    R.sup.11b : H                                                                                       R.sup.5 : CH.sub.3 (3- and 5-positions)                    -                                                                           M.p. 119-122.5° C.                                                                     Crystalline form: White powder                                  Solvent for recrystallization: Ethanol-diisopropyl ether                                                Form: Methanesulfonate                                Example 202                                                                     ##STR657##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                           R.sup.5 : --COOCH.sub.3 (2-position)                   -                                                                           M.p. 169-172° C.                                                                     Crystalline form: white powder                                    Solvent for recrystallization: Ethanol-water                                                            Form: Dimethanesulfonate                              __________________________________________________________________________

                                      TABLE 100                                    __________________________________________________________________________     Example 203                                                                     ##STR659##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 214-220° C.                                                                    Crystalline form: Pale yellow powder                                                             Form: Free                                       Solvent for recrystallization: Methanol                                        Example 204                                                                     ##STR661##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 195-197° C.                                                                    Crystalline form: Yellow powder                                                                Form: Free                                         Solvent for recrystallization: Dichloromethane-methanol                        Example 205                                                                     ##STR663##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                      -                                                                                       R.sup.5 : --(CH.sub.2).sub.4 -- (combined at 2- and 3-position                 s)                                                                   R.sup.11b : H                                                                      #STR664##                                                                   -                                                                           M.p. 151-153° C.                                                                      Crystalline form: Pale yellow powder                             Solvent for recrystallization: Water                                                                     Form: Free                                           __________________________________________________________________________

                                      TABLE 101                                    __________________________________________________________________________     Example 206                                                                     ##STR665##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                           R.sup.5 : n-Butyl (3-position)                         -                                                                           M.p. 148-150.4° C.                                                                   Crystalline form: Pale yellow powder                                                             Form: 2HCl                                      Solvent for recrystallization: Isopropyl alcohol-water-diethyl ether           Example 207                                                                     ##STR667##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                           R.sup.5 : (CH.sub.3).sub.3 C-- (2-position)                                    -                                                   M.p. 142-144.5° C.                                                                   Crystalline form: Pale yellow powder                                                            Form: Oxalate                                    Solvent for recrystallization: Isopropyl alcohol-water                         Example 208                                                                     ##STR669##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                         R.sup.5 : CH.sub.3 (3-position)                          -                                                                           M.p. 139.2-140.8° C.                                                                   Crystalline form: Pale yellow powder                            Solvent for recrystallization: Ethanol-water                                                          Form: Methanesulfonate                                  __________________________________________________________________________

                                      TABLE 102                                    __________________________________________________________________________     Example 209                                                                     ##STR671##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 O-- (3-position)                    -                                                                           M.p. 158-163° C.                                                                    Crystalline form: Pale yellow powder                                                             Form: 2HCl                                       Solvent for recrystallization: Ethanol-water-diethyl ether                                                   NMR (38)                                         Example 210                                                                     ##STR673##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                         R.sup.5 : n-Butyl (3-position)                           -                                                                           M.p. 84-86° C.                                                                      Crystalline form: Yellow amorphous                                                               Form: Free                                       Example 211                                                                     ##STR675##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                           R.sup.5 : n-Propyl (3-position)                        -                                                                           M.p. 121-124° C.                                                                    Crystalline form: Pale yellow powder                                                            Form: Dioxalate                                   Solvent for recrystallization: Isopropyl alcohol-water                         __________________________________________________________________________

                                      TABLE 103                                    __________________________________________________________________________     Example 212                                                                     ##STR677##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                      -                                                                                    R.sup.5 : CH.sub.3 (2- and 3-positions)                                 R.sup.11b : H                                                                      #STR678##                                                                   -                                                                           M.p. 140-150° C.                                                                    Crystalline form: Yellow powder                                                                NMR (39)                                           Solvent for recrystallization: Acetone-water                                                        Form: Methanesulfonate                                    Example 213                                                                     ##STR679##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      -                                                                                       R.sup.5 : --(CH.sub.2).sub.2 --CONH-- (combined at 2- and                      3-positions)                                                         R.sup.11b : H                                                                      #STR680##                                                                   -                                                                           M.p. 173-175° C.                                                                           Form: Dimethanesulfonate                                    Solvent for recrystallization: Diethyl ether-ethanol-water                       Crystalline form: Yellow powder                                              Example 214                                                                     ##STR681##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                          R.sup.5 : CH.sub.3 O (3-position)                       -                                                                           M.p. 168-172° C.                                                                      Crystalline form: Yellow powder                                  Solvent for recrystallization: Ethanol-diethyl ether                                                       Form: 2HCl                                         __________________________________________________________________________

                                      TABLE 104                                    __________________________________________________________________________     Example 215                                                                     ##STR683##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                          R.sup.5 : CH.sub.3 O (3-position)                       -                                                                           M.p. 155-16O° C.                                                                     NMR (40)                                                          Crystalline form: Pale yellow powder                                                                 Form: 2HCl                                               Solvent for recrystallization: Ethanol-water-isopropyl alcohol-diethyl         ether                                                                          Example 216                                                                     ##STR685##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     -                                                                                        R.sup.5 : CH.sub.3 O (3-position)                                   R.sup.11b : H                                                                      #STR686##                                                                   -                                                                           M.p. 163-165° C.                                                                       Crystalline form: Pale yellow powder                            Solvent for recrystallization: Ethanol-water                                                         Form: 2HCl                                               Example 217                                                                      R.sup.1 : CH.sub.3 R.sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.2 : CH.sub.3                                                                          R.sup.5 : CH.sub.3 O (3-position)                                   R.sup.11b : H                                                                      #STR687##                                                                   -                                                                           M.p. 190-193° C. (decomp.)                                                             Crystalline form: Yellow powder                                 Solvent for recrystallization: Ethanol-water                                                           Form: 2HCl                                             __________________________________________________________________________

                                      TABLE 105                                    __________________________________________________________________________      ##STR688##                                                                    __________________________________________________________________________     Example 218                                                                     ##STR689# R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                       R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 O (2-position)                      -                                                                           M.p. 174.4-176.5° C.                                                              Crystalline form: Yellow powder                                      Solvent for recrystallization: Ethanol-water-diethyl ether                                                Form: 2HCl                                          __________________________________________________________________________

                                      TABLE 106                                    __________________________________________________________________________      ##STR691##                                                                    __________________________________________________________________________     Example 219                                                                     ##STR692##    R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   R.sup.11b : H                                                                                              R.sup.5 : CH.sub.3 O-- (3-position)                                            -                                                M.p. 162-165° C.                                                                        Crystalline form: Pale yellow powder                           Solvent for recrystallization: Diethyl ether-water-ethanol                                                     Form: 2HCl                                     Example 220                                                                     ##STR694##    R4: H A: --CH.sub.2 -- m: 1                                       R.sup.11b : H                                                                                              R.sup.5 : CH.sub.3 O-- (3-position)                                            -                                                M.p. 206-211° C.                                                                      Crystalline form: Pale yellow powder                                                               Form: 2HCl                                   Solvent for recrystallization: Ethanol-water-diethyl ether-isopropyl           alcohol                                                                          NMR (41)                                                                     Example 221                                                                     ##STR696##    R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   R.sup.11b : H                                                                                            R.sup.5 : (CH.sub.3).sub.2 CHO-- (3-position)         -                                                                           M.p. 168-172° C.                                                                      Crystalline form: Yellow powder                                                                  Form: 2HCl                                     Solvent for recrystallization: Ethanol-water-isopropyl alcohol-diethyl         ether                                                                          __________________________________________________________________________

                                      TABLE 107                                    __________________________________________________________________________     Example 222                                                                     ##STR698##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                               R.sup.5 : (CH.sub.3).sub.2 CHO-- (3-position)                        R.sup.11b : H                                                                      #STR699##                                                                   -                                                                           M.p. 203-208° C.                                                                    Crystalline form: Pale yellow powder                                                             Form: 2HCl                                       Solvent for recrystallization: Ethanol-water-isopropyl alcohol-diethyl         ether                                                                            NMR (42)                                                                     Example 223                                                                     ##STR700##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 180-185° C.                                                                    Crystalline form: White powder                                                                 Form: 2HCl                                         Solvent for recrystallization: Ethanol-water                                                             NMR (43)                                             Example 224                                                                     ##STR702##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 180-190° C.                                                                    Crystalline form: Yellow powder                                                                Form: 2HCl                                         Solvent for recrystallization: Ethanol                                                              NMR (44)                                                  __________________________________________________________________________

                                      TABLE 108                                    __________________________________________________________________________     Example 225                                                                     ##STR704##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                      -                                                                                       R.sup.5 : CH.sub.3 O (3-position)                                    R.sup.11b : H                                                                      #STR705##                                                                   -                                                                           M.p. 157-160° C.                                                                    Crystalline form: Pale yellow powder                                                              Form: 2HCl                                      Solvent for recrystallization: Ethanol-water                                   Example 226                                                                     ##STR706##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 O (3-position)                      -                                                                           M.p. 171-174° C.                                                                    Crystalline form: Pale yellow powder                                                              Form: 2HCl                                      Solvent for recrystallization: Ethanol-water                                   Example 227                                                                     ##STR708##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                             R.sup.5 : CH.sub.3 O (3-position)                    -                                                                           M.p. 236-238° C.                                                                    Crystalline form: Pale yellow powder                                                              Form: HCl                                       Solvent for recrystallization: Ethanol-water                                   __________________________________________________________________________

                                      TABLE 109                                    __________________________________________________________________________     Example 228                                                                     ##STR710##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 161-165° C.                                                                    Crystalline form: Pale yellow powder                                                             Form: 2HCl                                       Solvent for recrystallization: Ethanol-water-diethyl ether-isopropyl           alcohol                                                                        Example 229                                                                     ##STR712##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                     R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 191-194° C.                                                                    Crystalline form: Pale yellow powder                                                             Form: 2HCl                                       Solvent for recrystallization: Ethanol-water                                   Example 230                                                                     ##STR714##  R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                               R.sup.5 : CH.sub.3 O (3-position)                                    R.sup.11b : H                                                                      #STR715##                                                                   -                                                                           M.p. 200-210° C. (decomp.)                                                            Crystalline form: Yellow powder                                                                NMR (45)                                         Solvent for recrystallization: Ethanol-water-diethyl ether                                                 Form: 2HCl                                         __________________________________________________________________________

                                      TABLE 110                                    __________________________________________________________________________     Example 231                                                                     ##STR716##    R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    -                                                                                        R.sup.5 : CH.sub.3 O (3-position)                                   R.sup.11b : H                                                                      #STR717##                                                                   -                                                                           M.p. 165-170° C.                                                                      Crystalline form: Yellow powder                                                                     Form: 2HCl                                  Solvent for recrystallization: Diethyl ether-ethanol-isopropyl alcohol-wat     er                                                                              NMR (46)                                                                      Example 232                                                                     ##STR718##    R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   R.sup.11b : H                                                                                              R.sup.5 : CH.sub.3 O (3-position)                   -                                                                           M.p. 150-170° C.                                                                      Crystalline form: Yellow powder                                                                     NMR (47)                                    Solvent for recrystallization: Isopropyl alcohol                                                             Form: Dimethanesulfonate                         Example 233                                                                     ##STR720##    R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                   R.sup.11b : H                                                                                              R.sup.5 : CH.sub.3 O (3-position)                   -                                                                           M.p. 166-169° C.                                                                      Crystalline form: Pale yellow powder                             Solvent for recrystallization: Ethanol-water                                                                 Form: 2HCl                                       __________________________________________________________________________

                                      TABLE 111                                    __________________________________________________________________________     Example 234                                                                     ##STR722##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 186-200° C. (decomp.)                                                             Crystalline form: Yellow powder                                                                Form: 3HCl                                      Solvent for recrystallization: Isopropyl alcohol                                                         NMR (48)                                             Example 235                                                                      R.sup.1 : CH.sub.3 R.sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.2 : CH.sub.3                                                                          R.sup.5 : CH.sub.3 O (3-position)                                   R.sup.11b : H                                                                       #STR724##                                                                  -                                                                           M.p. 204-210° C. (decomp.)                                                             Crystalline form: Yellow powder                                                                Form: HCl                                       Solvent for recrystallization: Ethanol-water-diethyl ether                                                  NMR (49)                                          Example 236                                                                      R.sup.1 : H R.sup.4 : H A: --CH.sub.2 -- m: 1                                R.sup.2 : H  R.sup.5 : CH.sub.3 O (3-position)                                   R.sup.11b : H                                                                       #STR725##                                                                  -                                                                           M.p. 157-160° C.                                                                     Crystaliine form: Yellow powder                                   Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           __________________________________________________________________________

                                      TABLE 112                                    __________________________________________________________________________     Example 237                                                                      R.sup.1 : H R.sup.4 : H A: --CH.sub.2 -- m: 1                                R.sup.2 : H  R.sup.5 : CH.sub.3 O (3-position)                                   R.sup.11b : H                                                                       #STR726##                                                                  -                                                                           M.p. 83.1-85.5° C.                                                                     Crystalline form: Yellow powder                                                                Form: Free                                      Solvent for recrystallization: Ethanol-diethyl ether-n-hexane                  Example 238                                                                     ##STR727##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                            R.sup.5 : F (3-position)                              -                                                                           M.p. 215-220° C.                                                                     Crystalline form: White powder                                                                 Form: 2HCl                                        Solvent for recrystallization: Ethanol-isopropyl alcohol-diethyl ether-wat     er                                                                              NMR (50)                                                                      Example 239                                                                     ##STR729##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 149-154° C.                                                                     Crystalline form: Pale yellow powder                                                             Form: 2HCl                                      Solvent for recrystallization: Ethanol-water-isopropyl alcohol-diethyl         ether                                                                            NMR (51)                                                                     __________________________________________________________________________

                                      TABLE 113                                    __________________________________________________________________________     Example 240                                                                     ##STR731##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                          R.sup.5 : Cl (3-position)                               -                                                                           M.p. 126-129° C.                                                                     Crystalline form: Pale yellow powder                                                             Form: Free                                      Solvent for recrystallization: Ethanol-isopropyl alcohol                       Example 241                                                                     ##STR733##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                          R.sup.5 : (CH.sub.3).sub.3 C-- (2-position)                                    -                                                    M.p. 181-183.8° C.                                                                   Crystalline form: Pale yellow powder                                                             Form: 2HCl                                      Solvent for recrystallization: Ethanol-water-diethyl ether                     Example 242                                                                      R.sup.1 : CH.sub.3 R.sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.2 : CH.sub.3                                                                          R.sup.5 : CH.sub.3 O (3-position)                                   R.sup.11b : H                                                                      #STR735##                                                                   -                                                                           M.p. 192-197° C. (decomp.)                                                             Crystalline form: Yellow powder                                                                Form: 2HCl                                      Solvent for recrystallization: Ethanol-water                                                           NMR (52)                                               __________________________________________________________________________

                                      TABLE 114                                    __________________________________________________________________________     Example 243                                                                     ##STR736##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                           R.sup.5 : C.sub.2 H.sub.5 O (3-position)                                       -                                                   M.p. 166-170° C.                                                                     Crystalline form: Pale yellow powder                                                             Form: 2HCl                                      Solvent for recrystallization: Ethanol-water                                   Example 244                                                                     ##STR738##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                           R.sup.5 : CF.sub.3 CH.sub.2 O (3-position)                                     -                                                   Crystalline form: Pale yellow powder                                                              Form: Dimethanesulfonate                                                                   NMR (53)                                        Solvent for recrystallization: Ethanol-water-diethyl ether-isopropyl           alcohol                                                                        Example 245                                                                     ##STR740##   R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 1                                    R.sup.11b : H                                                                                           R.sup.5 : CF.sub.3 CH.sub.2 O (3-position)                                     -                                                   M.p. 179-183° C.                                                                     Crystalline form: Pale yellow powder                                                             Form: 2HCl                                      Solvent for recrystallization: Isopropyl alcohol-ethanol-water-diethyl         ether                                                                          __________________________________________________________________________

                  TABLE 115                                                        ______________________________________                                          ##STR742##                                                                    ______________________________________                                         Example 246                                                                     ##STR743##    R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                    -                                                                                       R.sup.5 : CH.sub.3 O (3- and 5-positions)                            R.sup.11b : H                                                                        #STR744##                                                                 -                                                                           M.p. 182-185° C.                                                                      Crystalline form: Pale yellow powder                             Solvent for recrystallization: Ethanol-water                                                        Form: 2HCl, trans-form                                    Example 247                                                                     ##STR745##    R                                                                             .sup.4 : H A: --CH.sub.2 -- m: 2                                    -                                                                                       R.sup.5 : CH.sub.3 O (3- and 5-positions)                            R.sup.11b : H                                                                        #STR746##                                                                 -                                                                           M.p. 177-183° C.                                                                      Crystalhne form: Pale yellow powder                              Solvent for recrystalhzation Ethanol-water                                                          Form: 2HCl, cis-form                                      ______________________________________                                    

                                      TABLE 116                                    __________________________________________________________________________      ##STR747##                                                                    __________________________________________________________________________     Example 248                                                                                           RSTR748##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                              -                                                                             R.sup.11b : H                                                                                             R.sup.5 : CH.sub.3 O (3-position)                    -                                                                           M.p. 158-162° C.                                                                      Crystalline form: Pale yellow powder                                                            Form: 2HCl                                      Solvent for recrystallization: Ethanol-water-diethyl ether                       Example 249                                                                     -                                                                                                  R.sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                             R.sup.5 : CH.sub.3 O (3-position)                    -                                                                           M.p. 167-171° C. (decomp.)                                                               Crystalline form: Yellow powder                               Solvent for recrystallization: Ethanol-water                                                              Form: 3HCl                                            Example 250                                                                  R.sup.1 : CH.sub.3                                                                      R.sup.4: H                                                                           A: --CH.sub.2 --                                                                     m: 1                                                      R.sup.2 : CH.sub.3                                                                      R.sup.5 : CH.sub.3 O (3-position)                                        -                                                                             R.sup.11b : H                                                                       #STR752##                                                                  -                                                                           M.p. 137-140° C.                                                                      Crystalline form: Yellow powder                                  Solvent for recrystallization: Ethanol-water                                                           Form: Methanesulfonate                                 __________________________________________________________________________

                                      TABLE 117                                    __________________________________________________________________________     Example 251                                                                    R.sup.1 : (CH.sub.3).sub.3 C-- (3-position)                                                 R.sup.4: H                                                                           A: --CH.sub.2 --                                                                         m: 1                                              R.sup.2 : H                                                                         R.sup.5 : CH.sub.3 O (3-position)                                            -                                                                             R.sup.11b : H                                                                       #STR753##                                                                  -                                                                           M.p. 129-131° C.                                                                   Crystalline form: Pale yellow powder                                Solvent for recrystallization: Ethanol-water-diethyl ether-isopropyl           alcohol                                                                          Form: Dimethanesulfonate                                                       Example 252                                                                     -                                                                                                          RSTR754##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                      -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 230-231° C.                                                                   Crystalline form: Pale yellow powder                                Solvent for recrystallization: Ethanol-water                                                       Form: Dimethanesulfonate                                     Example 253                                                                     -                                                                                                          RSTR756##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                      -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 159-164° C. (decomp.)                                                             Crystalline form: Pale yellow powder                            Solvent for recrystallization: Ethanol-water                                                       Form: 2HCl                                                                             NMR (54)                                           __________________________________________________________________________

                                      TABLE 118                                    __________________________________________________________________________     Example 254                                                                                              RSTR758##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 202-205° C. (decomp.)                                                                Crystalline form: White powder                               Solvent for recrystallization: Ethanol-water                                                           Form: 2HCl                                               Example 255                                                                     -                                                                                                     RSTR760##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                       R.sup.5 : CH.sub.3 O (3-position)                          -                                                                           M.p. 115-120° C.                                                                      Crystalline form: Pale brown powder                                                             NMR (55)                                        Solvent for recrystallization: Ethanol-water-isopropyl alcohol-diethyl         ether                                                                            Form: Methanesulfonate                                                         Example 256                                                                     -                                                                                                     RSTR762##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                         R.sup.5 : CH.sub.3 O (3-position)                        -                                                                           M.p. 168.5-171.5° C.                                                                    Crystalline form: White powder                                 Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           __________________________________________________________________________

                                      TABLE 119                                    __________________________________________________________________________     Example 257                                                                                              RSTR764##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 163-166° C.                                                                      Crystalline form: White powder                                   Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                             Example 258                                                                     -                                                                                                     RSTR766##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 177.5-179° C.                                                                      Crystalline form: White powder                                 Solvent for recrystallization: Ethanol-water                                                          Form: 2HCl                                                Example 259                                                                     -                                                                                                     RSTR768##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 165-168.5° C.                                                                     Crystalline form: Pale yellow powder                                                           Form: 2HC1                                      Solvent for recrystallization: Ethanol-water-diethyl ether                     __________________________________________________________________________

                                      TABLE 120                                    __________________________________________________________________________     Example 260                                                                                              RSTR770##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 159-160° C.                                                                   Crystalline form: Pale yellow powder                                Solvent for recrystallization: Ethanol-water                                                                Form: 2HCl                                          Example 261                                                                     -                                                                                                     RSTR772##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 177-178.2° C.                                                                    Crystalline form: Pale yellow powder                             Solvent for recrystallization: Ethanol-water                                                                Form: 2HCl                                        S-(-)-compound: [α].sub.D.sup.22 : -5.75°(c = 2, water)            Example 262                                                                     -                                                                                                      RSTR774##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 173-175° C.                                                                      Crystalline form: Pale yellow powder                             Solvent for recrystallization: Ethanol-water                                                                Form: 2HCl                                        R-(+)-compound: [α].sub.D.sup.22 : +4.35°(c = 2, water)           __________________________________________________________________________

                                      TABLE 121                                    __________________________________________________________________________     Example 263                                                                                              RSTR776##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 168-170.5° C.                                                                 Crystalline form: White powder                                      Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                             Example 264                                                                     -                                                                                                     RSTR778##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 156-159° C.                                                                   Crystalline form: Pale yellow powder                                Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                             Example 265                                                                     -                                                                                                     RSTR780##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                                      R.sup.5 : CH.sub.3 O (3-position)                                      -                                                                             R.sup.11b : H                                                                       #STR781##                                                                  -                                                                           M.p. 176-179° C.                                                                   Crystalline form: Pale yellow powder                                Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           __________________________________________________________________________

                  TABLE 122                                                        ______________________________________                                         Example 266                                                                                                         RSTR782##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                                                  -                                         R.sup.5 : C.sub.2 H.sub.5 O (3-position)                                          -                                                                             R.sup.11b : H                                                                             #STR783##                                                            -                                                                           M.p. 159-161° C.                                                                   Crystalline form: Yellow powder                                                                   Form: 2HCl                                       Solvent for recrystallization: Ethanol-water-isopropyl alcohol-diethyl         ether                                                                            Example 267                                                                     -                                                                                                                     RSTR784##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                                                  -                                    R.sup.2 : CH.sub.3                                                                    R.sup.5 : CH.sub.3 O (3-position)                                          -                                                                             R.sup.11b : H                                                                         #STR785##                                                                -                                                                           M.p. 166-169° C.                                                                   Crystalline form: Yellow powder                                                                   Form: 2HCl                                       Solvent for recrystallization: Ethanol-water-diethyl ether-isopropyl           alcohol                                                                          Example 268                                                                     -                                                                                                                  RSTR786##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                                                  -                                       R.sup.5 : C.sub.2 H.sub.5 O (3-position)                                          -                                                                             R.sup.11b : H                                                                             #STR787##                                                            -                                                                           M.p. 215-217°C.                                                                    Crystalline form: White powder                                      Solvent for recrystallization: Ethanol-water                                                             Form: 2HCl                                           ______________________________________                                    

                                      TABLE 123                                    __________________________________________________________________________     Example 269                                                                                              RSTR788##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 174-177° C.                                                                  Crystalline form: Yellow powder                                                                    Form: Free                                       Solvent for recrystallization: Ethanol-water                                     Example 270                                                                     -                                                                                                     RSTR790##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                                       R.sup.5 : CH.sub.3 O (3-position)                                     -                                                                             R.sup.11b : H                                                                         #STR791##                                                                -                                                                           M.p. 202.5-205° C.                                                                Crystalline form: White powder                                                                     Form: 2HCl                                       Solvent for recrystallization: Ethanol-water                                     Example 271                                                                     -                                                                                                     RSTR792##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                                       R.sup.5 : CH.sub.3 O (3-position)                                     -                                                                             R.sup.11b : H                                                                         #STR793##                                                                -                                                                           M.p. 155-158° C.                                                                  Crystalline form: Yellow powder                                                                    Form: 2HCl                                       Solvent for recrystallization: Ethanol-water-diisopropyl alcohol-diethyl       ether                                                                          __________________________________________________________________________

                                      TABLE 124                                    __________________________________________________________________________     Example 272                                                                                              RSTR794##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 O (3-position)                     -                                                                           M.p. 202-204° C.                                                                 Crystalline form: Pale yellow powder                                                            Form: 2HCl                                           Solvent for recrystallization: Ethanol-water                                     Example 273                                                                     -                                                                                                     RSTR796##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                                   R.sup.5 : CH.sub.3 O (3-position)                                         -                                                                             R.sup.11b : H                                                                         #STR797##                                                                -                                                                           M.p. 163-165° C.                                                                 Crystalline form: Pale brown powder                                                             Form: 2HCl                                           Solvent for recrystallization: Ethanol-water                                     Example 274                                                                     -                                                                                                     RSTR798##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                            R.sup.5: CH.sub.3 O (3-position)                      -                                                                           M.p. 160-162° C.                                                                 Crystalline form: Pale yellow powder                                  Solvent for recrystallization: Ethanol-water                                                                 Form: 2HCl                                       __________________________________________________________________________

                                      TABLE 125                                    __________________________________________________________________________     Example 275                                                                                              RSTR800##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                           R.sup.5 : CH.sub.3 O (3-position)                      -                                                                           M.p. 158-160° C.                                                                      Crystalline form: Pale yellow powder                                                               Form: 2HCl                                   Solvent for recrystallization: Ethanol-diethyl ether-water                       Example 276                                                                     -                                                                                                     RSTR802##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                                        R.sup.5 : CH.sub.3 O (3-position)         -                                                                           M.p. 164-166° C.                                                                      Crystalline form: Pale yellow powder                                                               Form: 2HCl                                   Solvent for recrystallization: Ethanol-water                                   __________________________________________________________________________

Using the suitable starting compounds, the compounds as listed in Tables 126-128 are obtained in the same manner as in Example 5.

                  TABLE 126                                                        ______________________________________                                          ##STR804##                                                                    ______________________________________                                         Example 277                                                                     # RTR805##                                                                      .sup.4: H A: --CH.sub.2 -- m: 1                                                 -                                                                           R.sup.16a : C.sub.2 H.sub.5                                                              R.sup.11b : H                                                                              R.sup.5 : H                                              M.p. 130.5-132° C.                                                                 Crystalline form: Pale orange powder                                                               Form: Free                                      Solvent for recrystallization: Dimethylformamide-methanol                      ______________________________________                                    

                                      TABLE 127                                    __________________________________________________________________________      ##STR806##                                                                    __________________________________________________________________________     Example 278                                                                                              RSTR807##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                           R.sup.16a : C.sub.2 H.sub.5                                                             Z: O                                                                    R.sup.11b : H R.sup.5 : H                                                      M.p. 183.5-184° C. Crystalline form: White powder                     Solvent for recrystallization: Dichloromethane-ethanol                                                   Form: Free                                             Example 279                                                                     -                                                                                                     RSTR808##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                           R.sup.16a : C.sub.2 H.sub.5                                                             Z: O                                                                     -                                                                             R.sup.11b : H                                                                       #STR809##                                                                  -                                                                           M.p. 221° C. (decomp.)                                                                Crystalline form: Pale yellow powder                             Solvent for recrystallization: Diethyl ether-ethanol                                                     Form: 2HCl                                           __________________________________________________________________________

                  TABLE 128                                                        ______________________________________                                         Example 280                                                                     # RTR810##                                                                      .sup.4: H A: --CH.sub.2 -- m: 1                                                 -                                                                                   R.sup.16a : CH.sub.3                                                                        Z: O                                                      R.sup.11b : CH.sub.3                                                                     R.sup.5 : CH.sub.3 O (2-position)                                    M.p. 124-126.5° C.                                                                 Crystalline form: Pale yellow powder                                Solvent for recrystallization: Ethyl acetate-n-hexane                                                    Form: Free                                             Example 281                                                                     -                                                                                                               R.sup.4: H A: --CH.sub.2 -- m: 1                                               -                                                  R.sup.16a : C.sub.2 H.sub.5                                                                 Z: S                                                      R.sup.11b : H                                                                            R.sup.5 : CH.sub.3 O (2-position)                                    M.p. 156-159° C.                                                                   Crystalline form: Yellow powder                                     Solvent for recrystallization: Ethanol-dichloromethane                                                   Form: Free                                           ______________________________________                                    

Using the suitable starting compounds, the compounds as listed in Tables 129-149 are obtained in the same manner as in Example 8.

                  TABLE 129                                                        ______________________________________                                          ##STR812##                                                                    ______________________________________                                         Example 282                                                                                                        RSTR813##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                                                  -                                                   R.sup.5 : Isopropyl (2-position)                                         -                                                                             R.sup.11b : H                                                                         #STR814##                                                                -                                                                           M.p. 137-138° C.                                                                   Crystalline form: Pale yellow powder                                                               Form: Free                                        Example 283                                                                     -                                                                                                               R.sup.4: H A: --CH.sub.2 -- m: 1                                               -                                                   R.sup.5: Isopropyl (2-position)                                          -                                                                             R.sup.11b : H                                                                         #STR816##                                                                -                                                                           M.p. 197-198° C.                                                                     Crystalline form: White powder                                                                   Form: Free                                      Solvent for recrystallization: Dichloromethane-ethanol                         ______________________________________                                    

                                      TABLE 130                                    __________________________________________________________________________     Example 284                                                                     ##STR81 R#                                                                            .sup.4: H A: --CH.sub.2 -- m: 1                                           -                                                                             R.sup.11b : H                                                                                   #STR818##                                                                      #STR819##                                                      -                                                                           M.p. 240° C. (decomp.)                                                             Crystalline form: Pale yellow powder                                                            Form: 2HCl                                         Solvent for recrystallization: Ethanol-water                                     Example 285                                                                     -                                                                                                     RSTR820##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           - R.sup.11b : H                                                                                R.sup.5 : Isopropyl (2-position)                               -                                                                           M.p. 169.5-170° C.                                                               Crystalline form: White powder                                                                 Form: Free                                            Solvent for recrystallization: Ethanol                                           Example 286                                                                     -                                                                                                     RSTR822##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           - R.sup.11b : H                                                                                R.sup.5 : Isopropyl (2-position)                               -                                                                           Crystalline form: Pale brown powder                                                             Form: HCl                                                                              NMR (7)                                               __________________________________________________________________________

                                      TABLE 131                                    __________________________________________________________________________     Example 287                                                                                              RSTR824##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                  R.sup.5 : --(CH.sub.2).sub.4 OH (2-position)                    -                                                                           M.p. 170.5-175.5° C.                                                               Crystalline form: Pale yellow powder                                                            Form: Free                                         Solvent for recrystallization: Ethyl acetate-n-hexane                                                    NMR (8)                                                Example 288                                                                                            RSTR826##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                  R.sup.5 : H                                                     -                                                                           M.p. 201.5-202.5° C. (decomp.)                                                          Crystalline form: Pale yellow powder                           Solvent for recrystallization: Ethanol-dichloromethane                                                 Form: Free                                               Example 289                                                                                            RSTR828##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                  #STR829##                                                                      #STR830##                                                       -                                                                           M.p. 195-198° C.                                                                        Crystalline form: Yellow powder                                Solvent for recrystallization: Ethanol-water                                                           Form: 3HCl                                             __________________________________________________________________________

                                      TABLE 132                                    __________________________________________________________________________     Example 290                                                                                              RSTR831##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                          R.sup.11b : H                                                                                  R.sup.5 : Isopropyl (2-position)                                -                                                                           M.p. 101-103.5° C.                                                                 Crystalline form: Yellow amorphous Form: Free                         Example 291                                                                                            RSTR833##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                  #STR834##                                                                      #STR835##                                                       -                                                                           M.p. 148.2-153° C.                                                                 Crystalline form: Pale brown powder                                                             Form: 3HC1                                         Solvent for recrystallization: Ethanol-diethyl ether                                                          NMR (10)                                          Example 292                                                                                            RSTR836##                                                                    .sup.4: H A: --CH.sub.2 -- m: 1                           -                                                                             R.sup.11b : H                                                                                  #STR837##                                                                      #STR838##                                                       -                                                                           M.p. 184-187° C.                                                                  Crystalline form: Pale yellow powder                                 Solvent for recrystallization: Ethanol-water-diethyl ether                                                    Form: 2HCl                                      __________________________________________________________________________

                  TABLE 133                                                        ______________________________________                                         Example 293                                                                                                            RSTR839##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1           R.sup.11b : H                                                                                             R.sup.5 : F (2-position)                             -                                                                           M.p. 151-154° C. Crystalline form: White powder Form: HCl                 Solvent for recrystallization: Ethanol-water-diethyl ether-isopropyl         alcohol                                                                          Example 294                                                                                                            RSTR841##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1         R.sup.11b : H                                                                                             R.sup.5 : Cl (2-position)                            -                                                                           M.p. 207-209° C. Crystalline form: White powder Form: Free               Solvent for recrystallization: Ethyl acetate-n-hexane                           Example 295                                                                                                            RSTR843##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1         R.sup.11b : H                                                                                             R.sup.5 : Cl (2-position)                            -                                                                           M.p. 164-166° C. Crystalline form: Pale yellow powder                     Solvent for recrystallization: Methanol-diethyl ether Form: HCl              ______________________________________                                    

                  TABLE 134                                                        ______________________________________                                         Example 296                                                                                                            RSTR845##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                                                 - R.sup.11b : H                                                                R.sup.5 : F (2-position)                  -                                                                           M.p. 141-141.5° C. Crystalline form: White powder Form: Free             Solvent for recrystallization: Dichloromethane-diethyl ether                    Example 297                                                                                                            RSTR847##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                                                 - R.sup.11b : H                                                                R.sup.5 : CH.sub.3 O (2-position                                             )                                         -                                                                           M.p. 186.5-191° C. (decomp.) Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-diethyl ether                           Form: Methanesulfonate                                                          Example 298                                                                                                            RSTR849##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                                                 - R.sup.11b : H                                                                R.sup.5 : CH.sub.3 (2-position)         -                                                                           Crystalline form: Pale yellow amorphous Form: Free NMR (15)                    ______________________________________                                    

                                      TABLE 135                                    __________________________________________________________________________     Example 299                                                                                                                     RSTR851##                                                                    .sup.4 : H A: --CH.sub.2                                                       -- m: 1                           R.sup.11b : H                                                                                            R.sup.5 : CH.sub.3 (2 position)                       -                                                                           Crystalline form: Pale yellow amorphous Form: Free NMR (16)                    Example 300                                                                                                                     RSTR853##                                                                    .sup.4 : H A: --CH.sub.2                                                       -- m: 1                           R.sup.11b : H                                                                                            R.sup.5 : C.sub.2 H.sub.5 O (2-position)                                       -                                                  M.p. 202.5-203° C. Crystalline form: Pale powder                          Solvent for recrystallization: Ethanol-isopropyl alcohol-water-diethyl       ether                                                                            Form: Methanesulfonate                                                       Example 301                                                                                                                     RSTR855##                                                                    .sup.4 : H A: --CH.sub.2                                                       -- m: 1                           R.sup.11b : H                                                                                            #STR856##                                                                      #STR857##                                             -                                                                           M.p. 186-189° C. Crystalline form: Pale yellow powder                     Solvent for recrystallization: Water-ethanol-diethyl ether Form:             __________________________________________________________________________     3HCl                                                                      

                                      TABLE 136                                    __________________________________________________________________________     Example 302                                                                                                RSTR858##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                       R.sup.11b : H                                                                                     R.sup.5 : CH.sub.3 O (3-position)                            -                                                                           M.p. 135-145° C. Crystalline form: White powder Form: Free               Solvent for recrystallization: Ethanol-dichloromethane NMR (17)               Example 303                                                                                                RSTR860##                                                                    .sup.4 : H                                                                       m: 1 61##                                            R.sup.11b : H                                                                                     R.sup.5 : Cl (2-position)                                    -                                                                           Crystalline form: Pale yellow amorphous Form: Free NMR (18)                    Example 304                                                                                                RSTR863##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                       R.sup.11b : H                                                                                     #STR864##                                                                      #STR865##                                                    -                                                                           M.p. 146.5-150° C. Crystalline form: White powder                         Solvent for recrystallization: Ethanol-water Form: 2HCl                      __________________________________________________________________________

                                      TABLE 137                                    __________________________________________________________________________     Example 305                                                                                              RSTR866##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 2                         R.sup.11b : H                                                                                   R.sup.5 : CH.sub.3 O (2- and 6-positions)                      -                                                                           M.p. 115-120° C. Crystalline form: Pale yellow powder NMR (19)           Solvent for recrystallization: Ethanol-diethyl ether Form: Methanesulfona     te                                                                             Example 306                                                                                              RSTR868##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR869##                                                                      #STR870##                                                      -                                                                           M.p. 207-208.5° C. Crystalline form: White powder                         Solvent for recrystallization: Diethyl ether-ethanol Form: Methanesulfon     ate                                                                            Example 307                                                                                             RSTR871##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                          R.sup.11b : H                                                                                  #STR872##                                                                      #STR873##                                                       -                                                                           Crystalline form: Pale yellow amorphous Form: Free NMR (20)                    __________________________________________________________________________

                                      TABLE 138                                    __________________________________________________________________________     Example 308                                                                                              RSTR874##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR875##                                                                      #STR876##                                                      -                                                                           M.p. 139-141° C. Crystalline form: Yellow powder                          Solvent for recrystallization: Ethanol Form: Methanesulfonate                Example 309                                                                                              RSTR877##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR878##                                                                      #STR879##                                                      -                                                                           M.p. 194-197° C. Crystalline form: White powder                           Solvent for recrystallization: Ethanol-water Form: Dimethanesulfonate        Example 310                                                                                              RSTR880##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR881##                                                                      #STR882##                                                      -                                                                           M.p. 218-220° C. Crystalline form: Pale yellow powder                     Solvent for recrystallization: Ethanol-water Form: Dimethanesulfonate        __________________________________________________________________________

                                      TABLE 139                                    __________________________________________________________________________     Example 311                                                                                              RSTR883##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR884##                                                                      #STR885##                                                      -                                                                           M.p. 182.5-186° C. Crystalline form: Yellow powder                        Solvent for recrystallization: Ethanol-diethyl ether Form: 2HCl              Example 312                                                                    R.sup.1 : CH.sub.3                                                                     R.sup.4 : H                                                                             A: --CH.sub.2 --                                                                      m: 1                                                     R.sup.2 : CH.sub.3                                                             R.sup.11b : H                                                                                   #STR886##                                                                      #STR887##                                                      -                                                                           Crystalline form: White powder Form: Methanesulfonate                            Solvent for recrystallization: Ethanol-diethyl ether NMR (21)                Example 313                                                                                              RSTR888##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR889##                                                                      #STR890##                                                      -                                                                           M.p. 140-141° C. Crystalline form: White powder Form: Methanesulfon     ate                                                                             Solvent for recrystallization: Ethanol-isopropyl alcohol-diethyl              __________________________________________________________________________     ether                                                                     

                                      TABLE 140                                    __________________________________________________________________________     Example 314                                                                                              RSTR891##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR892##                                                                      #STR893##                                                      -                                                                           M.p. 166-177° C. Crystalline form: White powder NMR (22)                  Solvent for recrystallization: Ethanol-diethyl ether Form: 2HCl              Example 315                                                                                              RSTR894##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR895##                                                                      #STR896##                                                      -                                                                           M.p. 156-157° C. Crystalline form: White powder                           Solvent for recrystallization: Ethanol Form: Free                            Example 316                                                                                              RSTR897##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR898##                                                                      #STR899##                                                      -                                                                           M.p. 191-192° C. Crystalline form: White powder Form: 3HCl               Solvent for recrystallization: Ethanol-water-isopropyl alcohol                __________________________________________________________________________

                                      TABLE 141                                    __________________________________________________________________________     Example 317                                                                                              RSTR900##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR901##                                                                      #STR902##                                                      -                                                                           Crystalline form: Pale yellow amorphous Form: Free NMR (23)                    Example 318                                                                                              RSTR903##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR904##                                                                      #STR905##                                                      -                                                                           Crystalline form: Colorless amorphous Form: Free NMR (24)                      Example 319                                                                                              RSTR906##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                   #STR907##                                                                      #STR908##                                                      -                                                                           M.p. 178-180° C. Crystalline form: White powder Form: 3HCl               Solvent for recrystallization: Ethanol-isopropanol-diethyl ether-water        __________________________________________________________________________

                                      TABLE 142                                    __________________________________________________________________________     Example 320                                                                                                           RSTR909##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1            R.sup.11b : H                                                                                                #STR910##                                                                      #STR911##                                         -                                                                           Crystalline form: Pale yellow amorphous Form: Free NMR (25)                    Example 321                                                                                                           RSTR912##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1            R.sup.11b : H                                                                                                #STR913##                                                                      #STR914##                                         -                                                                           M.p. 198-201° C. Crystalline form: Pale yellow powder Form: 2HCl         Solvent for recrystallization: Ethanol-water                                  Example 322                                                                                                           RSTR915##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1            R.sup.11b : H                                                                                                #STR916##                                                                      #STR917##                                         -                                                                           M.p. 177-178° C. Crystalline form: White powder Form: Free               Solvent for recrystallization: Diethyl ether-ethanol-dichloromethane          __________________________________________________________________________

                                      TABLE 143                                    __________________________________________________________________________     Example 323                                                                                                  RSTR918##                                                                    .sup.4 : H m: 1                                                                  #STR919##                                          R.sup.11b : H                                                                          #STR920##                                                               -                                                                           M.p. 234-235° C. Crystalline form: White powder Form: Free               Solvent for recrystallization: Ethyl acetate-n-hexane                         Example 324                                                                                                  RSTR921##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                     R.sup.11b : H R.sup.5 : CH.sub.3 O (2-position)                                                               #STR922##                                        -                                                                           M.p. 206-207° C. Crystalline form: Pale yellow powder Form: Free         Solvent for recrystallization: Dichloromethane-ethanol-diethyl ether          Example 325                                                                                                  RSTR923##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                     R.sup.11b : H R.sup.5 : n-Butyl (2-position)                                                                  #STR924##                                        -                                                                           M.p. 195.5-196.5° C. Crystalline form: Pale yellow needles               Solvent for recrystallization: Ethanol-dichloromethane Form: Free             __________________________________________________________________________

                                      TABLE 144                                    __________________________________________________________________________     Example 326                                                                                                        RSTR925##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1               R.sup.11b : H                                                                                             #STR926##                                                                      #STR927##                                            -                                                                           M.p. 134-136° C. (decomp.) Crystalline form: Yellow powder Form:        Free                                                                             Solvent for recrystallization: Dichloromethane-diisopropyl ether             Example 327                                                                                                        RSTR928##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1               R.sup.11b : H                                                                                             #STR929##                                                                      #STR930##                                            -                                                                           M.p. 207.6-214° C. (decomp.) Crystalline form: White powder              Solvent for recrystallization: Dichloromethane NMR (26) Form: Free            Example 328                                                                                                        RSTR931##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1               R.sup.11b : H R.sup.5 : n-Butyl (2-position)                                                              #STR932##                                            -                                                                           M.p. 191-193° C. Crystalline form: Pale yellow powder                     Solvent for recrystallization: Ethanol-dichloromethane Form: Free            __________________________________________________________________________

                                      TABLE 145                                    __________________________________________________________________________     Example 329                                                                                              RSTR933##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                         R.sup.11b : H                                                                                                #STR934##                                                                      #STR935##                                         -                                                                           M.p. 112-114° C. Crystalline form: Pale yellow powder Form: Free         Solvent for recrystallization: Ethyl acetate-diethyl ether                    Example 330                                                                                                           RSTR936##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1            R.sup.11b : H                                                                                                #STR937##                                                                      #STR938##                                         -                                                                           M.p. 209-211° C. Crystalline form: Yellow powder                          Solvent for recrystallization: Ethanol-water Form: 3HCl                      Example 331                                                                                                           RSTR939##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1            R.sup.11b : H R.sup.5 : CH.sub.3 O (2-position)                                                              #STR940##                                         -                                                                           M.p. 208-210° C. Crystalline form: Pale yellow powder                     Solvent for recrystallization: Ethanol-dichloromethane Form: Free            __________________________________________________________________________

                  TABLE 146                                                        ______________________________________                                         Example 332                                                                                                      RSTR941##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                 R.sup.11b : H R.sup.5 : CH.sub.3 O  (2-position)                                                    #STR942##                                                  -                                                                           M.p. 200-203° C. Crystalline form: Yellow powder Form: Free              Solvent for recrystallization: Ethanol-isopropyl alcohol-dichloromethane        Example 333                                                                                                      RSTR943##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1               R.sup.11b : H R.sup.5 : CH.sub.3 O  (2-position)                                                    #STR944##                                                  -                                                                           M.p. 196-197° C. Crystalline form: White powder Form: Free               Solvent for recrystallization: Ethanol-dichloromethane                          Example 334                                                                                                      RSTR945##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1               R.sup.11b : H R.sup.5 : CH.sub.3 O  (2-position)                                                    #STR946##                                                  -                                                                           M.p. 203-204° C. Crystalline form: White powder Form: Free               Solvent for recrystallization: Dichloromethane-ethanol-isopropyl              ______________________________________                                         alcohol                                                                   

                  TABLE 147                                                        ______________________________________                                         Example 335                                                                                                       RSTR947##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                R.sup.11b : H R.sup.5 : C.sub.2 H.sub.5 O  (2-position)                                              #STR948##                                                 -                                                                           M.p. 206-208° C. Crystalline form: Pale yellow powder Form: Free         Solvent for recrystallization: Dichloromethane-n-hexane                         Example 336                                                                                                       RSTR949##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1              R.sup.11b : H R.sup.5 : C.sub.2 H.sub.5 O  (2-position)                                              #STR950##                                                 -                                                                           M.p. 190-192° C. Crystalline form: Pale yellow needles Form: Free        Solvent for recrystallization: Chloroform-ethyl acetate                         Example 337                                                                                                       RSTR951##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1              R.sup.11b : H R.sup.5 : C.sub.2 H.sub.5 O  (2-position)                                              #STR952##                                                 -                                                                           M.p. 207-209° C. Crystalline form: Pale yellow powder Form: Free         Solvent for recrystallization: Ethyl acetate-diisoropyl ether                 ______________________________________                                    

                                      TABLE 148                                    __________________________________________________________________________     Example 338                                                                                                 RSTR953##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                      R.sup.11b : H R.sup.5 : Isopropyl (2-position)                                                     #STR954##                                                   -                                                                           M.p. 199-200.5° C. Crystalline form: White powder                         Solvent for recrystallization: Methanol-dimethylformamide Form: Free         Example 339                                                                                                 RSTR955##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                      R.sup.11b : H R.sup.5 : C.sub.2 H.sub.5 O (2-position)                                             #STR956##                                                   -                                                                           M.p. 204-206° C. Crystalline form: Pale yellow powder Form: Free         Solvent for recrystallization: Ethanol-dichloromethane                        Example 340                                                                                                 RSTR957##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                      R.sup.11b : H R.sup.5 : C.sub.2 H.sub.5 O (2-position)                                             #STR958##                                                   -                                                                           M.p. 115-117° C. Crystalline form: Pale yellow powder Form: Free         Solvent for recrystallization: Ethyl acetate-diisopropyl ether                __________________________________________________________________________

                  TABLE 149                                                        ______________________________________                                         Example 341                                                                                                       RSTR959##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1                R.sup.11b : H R.sup.5 : C.sub.2 H.sub.5 O  (2-position)                                              #STR960##                                                 -                                                                           M.p. 225-227° C. Crystalline form: Pale yellow powder Form: Free         Solvent for recrystallization: Ethyl acetate-diisopropyl ether                  Example 342                                                                                                       RSTR961##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1              R.sup.11b : H R.sup.5 : C.sub.2 H.sub.5 O  (2-position)                                              #STR962##                                                 -                                                                           M.p. 196.5-198° C. Crystalline form: Pale yellow powder                   Solvent for recrystallization: Chloroform-ethyl acetate Form: Free             Example 343                                                                                                       RSTR963##                                                                    .sup.4 : H A: --CH.sub.2 -- m: 1              R.sup.11b : H R.sup.5 : CH.sub.3 O  (2-position)                                                     #STR964##                                                 -                                                                           M.p. 192-194° C. Crystalline form: Pale yellow powder                     Solvent for recrystallization: Ethyl acetate-diisopropyl ether Form:         Free                                                                           ______________________________________                                    

¹ H-NMR spectrum (NMR (1) to NMR (55)) as described in Tables 50-149 are as follows:

NMR (1) (CDCl₃) δppm: 2.33 (3H, s), 2.45 (4H, t, J=5 Hz), 3.6-3.8 (4H, m), 4.85 (2H, s), 7.09 (2H, d, J=9 Hz), 7.3-7.55 (2H, m), 7.50 (1H, d, J=15 Hz), 7.8-7.95 (2H, m), 7.93 (1H, d, J=15 Hz), 8.10 (2H, d, J=9 Hz), 9.88 (1H, br); NMR (2) (DMSO-d₆) δppm: 1.35-1.8 (2H, m), 2.0-2.3 (2H, m), 2.6-3.9 (11H, m), 2.81 (3H, s), 4.1-4.3 (1H, m), 4.5-4.7 (1H, m), 5.08 (2H, s), 7.15 (2H, d, J=9 Hz), 7.3-7.55 (3H, m), 7.76 (1H, d, J=14 Hz), 7.77 (1H, d, J=8.5 Hz), 7.98 (1H, d, J=8 Hz), 8.05 (2H, d, J=9 Hz), 12.67 (1H, br); NMR (3) (DMSO-d₆) δppm: 2.32 (3H, s), 2.45-4.50 (20H, m, 2.50 (s)), 5.14 (2H, s), 7.04 (1H, d, J=9.3 Hz), 7.26-7.52 (3H, m), 7.70-8.10 (5H, m), 11.30-12.35, 12.35-13.20 (all 3H, br); NMR (4) (DMSO-d₆) δppm: 2.60-4.50 (20H, m), 5.23 (2H, s), 7.20-7.55 (4H, m), 7.70-8.10 (5H, m), 11.30-13.20 (3H, br); NMR (5) (DMSO-d₆) δppm: 0.926 (3H, t, J=7.4 Hz), 1.5-1.9 (4H, m), 2.05-2.3 (2H, m), 2.6-2.8 (3H, m), 2.81 (3H, s), 3.0-3.3 (1H, m), 3.3-3.9 (9H, m), 4.15-4.35 (1H, m), 4.5-4.8 (1H, m), 5.12 (2H, s), 7.02 (1H, d, J=8.6 Hz), 7.27-7.47 (3H, m), 7.74-7.99 (4H, m), 7.91 (1H, d, J=15 Hz), 11.5-13.0 (3H, br); NMR (6) (DMSO-d₆) δppm: 0.93 (3H, t, J=7.4 Hz), 1.55-1.75 (2H, m), 2.6-2.8 (4H, m), 2.79 (3H, s), 3.0-4.15 (14H, m), 4.2-4.4 (1H, m), 5.12 (2H, s), 7.03 (1H, d, J=8.5 Hz), 7.25-7.55 (2H, m), 7.45 (1H, s), 7.75-7.9 (4H, m), 7.79 (1H, d, J=8.5 Hz); NMR (7) (DMSO-d₆) δppm: 1.25 (6H, d, J=7 Hz), 1.3-2.0 (4H, m), 2.6-3.5 (6H, m), 5.12 (2H, s), 6.77 (1H, dd, J=6 Hz, J=15.5 Hz), 7.00 (1H, d, J=8.5 Hz), 7.17 (1H, d, J=15.5 Hz), 7.25-7.5 (2H, m), 7.7-8.05 (4H, m), 9.14 (2H, br), 12.73 (1H, br); NMR (8) (CDCl₃) δppm: 1.62 (3H, t, J=7.3 Hz), 1.76-2.03 (4H, m), 2.85-3.09 (2H, m), 3.95-4.11 (2H, m), 4.52 (2H, q, J=7.3 Hz), 4.88 (2H, s), 5.28 (1H, brs), 6.98 (1H, d, J=7.5 Hz), 7.32-7.43 (1H, m), 7.43-7.55 (1H, m), 7.56 (1H, d, J=15.2 Hz), 7.77-7.93 (2H, m), 8.00-8.12 (2H, m), 8.35 (1H, d, J=15.2 Hz), 10.85 (1H, brs); NMR (9) DMSO-d₆) δppm: 0.93 (3H, t, J=7.4 Hz), 1.5-1.8 (2H, m), 1.8-2.2 (4H, m), 2.69 (2H, t, J=7.4 Hz), 2.8 (3H, s), 3.0-4.3 (12H, m), 4.3-4.6 (1H, m), 5.13 (2H, s), 7.03 (1H, d, J=8.6 Hz), 7.17 (1H, d, J=15.1 Hz), 7.30 (1H, t, J=7 Hz), 7.74-7.99 (5H, m), 11.5-12.3 (1H, br), 12.3-13.3 (1H, br); NMR (10) DMSO-d₆) δppm: 1.56-1.91 (4H, m), 2.70-2.90 (7H, m), 3.10-3.52 (8H, m), 5.14 (2H, s), 6.65-6.75 (1H, m), 6.99-7.15 (2H, m), 7.28-7.40 (1H, m), 7.40-7.52 (1H, m), 7.52-7.60 (2H, m), 7.72-7.85 (1H, m), 7.90-8.08 (4H, m), 10.90-13.18 (3H, m); NMR (11) (DMSO-d₆) δppm: 1.40-1.89 (2H, m), 1.96-2.32 (2H, m), 2.58-2.96 (4H, m), 2.96-3.83 (10H, m), 3.89 (3H, s), 4.06-4.34 (1H, m), 4.42-4.71 (1H, m), 5.08 (2H, s), 7.07 (1H, d, J=8.5 Hz), 7.31 (11H, t, J=7.0 Hz), 7.38-7.69 (3H, m), 7.69-7.92 (3H, m), 7.98 (1H, d, J=8.5 Hz), 11.76 (2H, br), 12.71 (1H, br), NMR (12) (DMSO-d₆) δppm: 1.40-1.85 (2H, m), 2.00-2.23 (2H, m), 2.40 (3H, s), 2.60-2.88 (1H, m), 2.81 (3H, s), 3.00-3.80 (10H, m), 3.89 (3H, s), 4.10-4.30 (1H, m), 4.48-4.78 (1H, m), 5.06 (2H, s), 7.04 (1H, d, J=8.5 Hz), 7.21-7.31 (1H, m), 7.40 (1H, d, J=15.2 Hz), 7.52-7.60 (1H, m), 7.60-7.88 (4H, m), 11.02-12.33 (2H, m), 12.33-12.80 (1H, m); NMR (13) (DMSO-d₆) δppm: 2.40 (3H, s), 2.81 (3H, s), 2.90-4.35 (15H, m), 3.89 (3H, s), 5.07 (2H, s), 6.99-7.12 (1H, m), 7.12-7.35 (2H, m), 7.52-7.60 (1H, m), 7.60-7.91 (4H, m), 11.00-13.28 (3H, m); NMR (14) (CDCl₃) δppm: 1.31-1.64 (2H, m), 1.77-2.07 (2H, m), 2.21-2.87 (10H, m), 2.29 (3H, s), 2.67 (3H, s), 3.06-3.26 (1H, m), 3.96-4.28 (1H, m), 4.10 (3H, s), 4.62-4.78 (1H, m), 4.87 (2H, s), 7.07 (1H, d, J=8.1 Hz), 7.14-7.32 (2H, m), 7.52 (1H, d, J=14.9 Hz), 7.61-7.77 (3H, m), 7.91 (1H, d, J=14.9 Hz); NMR (15) (CDCl₃) δppm: 1.20-2.16 (4H, m), 2.31-2.72 (3H, m), 2.44 (3H, s), 2.72-3.34 (2H, m), 4.85 (2H, s), 6.76-7.06 (3H, m), 7.21-7.58 (2H, m), 7.72-8.00 (4H, m); NMR (16) (CDCl₃) δppm: 1.43-2.13 (4H, m), 2.28 (6H, s), 2.45 (3H, s), 2.53-3.28 (5H, m), 3.56-4.56 (2H, m), 4.86 (2H, s), 6.80-7.11 (3H, m), 7.28-7.53 (2H, m), 7.74-7.93 (4H, m); NMR (17) (CDCl₃) δppm: 1.3-1.5 (2H, m), 1.7-1.9 (2H, m), 2.6-2.8 (2H, m), 2.8-3.3 (2H, m), 3.90 (3H, s), 4.80 (2H, s), 6.5-6.65 (2H, m), 6.73 (1H, d, J=15.5 Hz), 6.87 (1H, dd, J=15.5 Hz, J=6 Hz), 7.3-7.55 (2H, m), 7.6-7.95 (4H, m); NMR (18) (CDCl₃) δppm: 1.12 (3H, t, J=5.9 Hz), 1.28-3.78 (11H, m), 4.97 (1H, t, J=5.3 Hz), 6.68-7.53 (5H, m), 7.70-8.14 (4H, m); NMR (19) (DMSO-d₆) δppm: 1.29-2.11 (4H, m), 2.32 (3H, s), 2.60-3.08 (3H, m), 3.08-3.56 (3H, m), 3.91 (6H, s), 4.85 (2H, s), 6.73-6.93 (1H, m), 7.19-7.54 (5H, m), 7.71-7.83 (1H, m), 7.93-8.05 (1H, m), 8.29-8.80 (1H, m), 12.14 (1H, brs); NMR (20) (CDCl₃) δppm: 1.86-2.13 (2H, m), 2.39 (3H, s), 2.48-3.06 (12H, m), 3.82 (3H, s), 4.87 (2H, s), 6.82-8.09 (9H, m), 7.04 (1H, s), 7.21 (1H, s); NMR (21) (DMSO-d₆) δppm: 1.4-2.2 (6H, m), 2.35 (3H, s), 2.65-2.85 (2H, m), 2.95-4.05 (14H, m), 5.07 (2H, s), 6.78 (1H, dd, J=7 Hz, J=15.5 Hz), 7.02 (1H, d, J=8.5 Hz), 7.16 (1H, d, J=15.5 Hz), 7.26 (1H, d, J=3.5 Hz), 7.50 (1H, d, J=3.5 Hz), 7.8-8.0 (2H, m), 9.58 (1H, br), 12.45 (1H, br); NMR (22) (DMSO-d₆) δppm: 1.33-1.71 (5H, m), 1.80-2.00 (1H, m), 2.00-2.21 (2H, m), 2.65-2.77 (2H, m), 2.80 (3H, s), 2.88-3.10 (4H, m), 3.10-4.00 (14H, m), 4.00-4.23 (1H, m), 4.47-4.66 (1H, m), 5.13 (2H, s), 6.71-6.87 (1H, m), 6.98-7.09 (1H, m), 7.09-7.22 (1H, m), 7.26-7.40 (1H, m), 7.40-7.52 (1H, m), 7.72-7.83 (1H, m), 7.83-7.97 (2H, m), 7.97-8.08 (1H, m), 11.32-12.55 (2H, m), 12.70 (1H, brs); NMR (23) (CDCl₃) δppm: 1.43-2.28 (12H, m), 2.28-3.01 (13H, m), 3.23-3.56 (2H, m), 3.56-4.09 (5H, m), 4.87 (2H, s), 6.74-7.02 (3H, m), 7.22-7.53 (2H, m), 7.70-7.97 (4H, m); NMR (24) (CDCl₃) δppm: 1.43-2.18 (12H, m), 2.37-2.68 (8H, m), 2.86 (2H, t, J=7.7 Hz), 2.97-3.16 (2H, m), 3.25-3.53 (2H, m), 3.56-3.80 (4H, m), 3.82-4.03 (2H, m), 4.85 (2H, s), 6.79-7.00 (3H, m), 7.22-7.53 (2H, m), 7.68-7.93 (4H, m); NMR (25) (CDCl₃) δppm: 1.48-3.22 (19H, m), 1.62 (3H, t, J=7.4 Hz), 3.57-3.78 (4H, m), 4.54 (2H, q, J=7.4 Hz), 4.89 (2H, s), 6.99 (1H, d, J=8.5 Hz), 7.22-7.53 (3H, m), 7.59 (1H, d, J=15.2 Hz), 7.76-7.90 (2H, m), 7.92-8.09 (1H, m), 8.36 (1H, d, J=15.2 Hz); NMR (26) (DMSO-d₆) δppm: 2.65-2.8 (1H, m), 2.9-3.05 (1H, m), 3.3-3.45 (2H, m), 3.8 (1H, m), 4.65 (2H, br), 5.11 (2H, s), 7.06 (1H, d, J=8.5 Hz), 7.25-7.5 (2H, m), 7.64 (1H, d, J=15.5 Hz), 7.75-7.9 (3H, m), 7.95-8.2 (4H, m), 8.66 (2H, br), 12.58 (1H, br); NMR (27) (CDCl₃) δppm: 1.36 (3H, t, J=7.5 Hz), 2.6-3.6 (6H, m), 2.86 (2H, q, J=7.5 Hz), 4.05 (1H, m), 4.50 (1H, m), 4.87 (2H, s), 6.93 (1H, d, J=8 Hz), 7.35-7.55 (3H, m), 7.8-8.0 (1H, m), 9.66 (1H, br); NMR (28) (DMSO-d₆) δppm: 1.67-1.97 (2H, m), 2.80 (3H, s), 2.88-4.35 (17H, m), 3.90 (3H, s), 5.10 (2H, s), 7.08 (1H, d, J=8.6 Hz), 7.20-7.66 (4H, m), 7.66-7.95 (3H, m), 7.99 (1H, d, J=7.1 Hz), 12.70 (1H, s); NMR (29) (DMSO-d₆) δppm: 2.05-2.35 (2H, m), 2.55-4.18 (22H, m), 4.18-4.42 (1H, m), 5.09 (2H, s), 7.07 (1H, d, J=8.6 Hz), 7.27-7.57 (4H, m), 7.74-7.77 (3H, m), 7.98 (1H, d, J=7.1 Hz), 11.52 (2H, br), 12.55 (1H, br); NMR (30) (CDCl₃) δppm: 1.1-1.4 (3H, m), 1.37 (3H, t, J=7.5 Hz), 2.5-2.8 (2H, m), 2.86 (2H, q, J=7.5 Hz), 2.9-3.1 (3H, m), 3.2-3.6 (2H, m), 3.8-4.1 (1H, m), 4.5-4.8 (1H, m), 4.87 (2H, s), 5.35 (1H, br), 6.93 (1H, d, J=9 Hz), 7.25-7.6 (3H, m), 7.75-8.05 (5H, m), 9.60 (1H, br); NMR (31) (DMSO-d₆) δppm: 0.74-0.91 (3H, m), 1.12-1.44 (6H, m), 1.50-1.71 (2H, m), 2.55-2.90 (3H, m), 2.79 (3H, s), 2.90-3.80 (13H, m), 3.80-4.12 (4H, m), 4.19-4.42 (1H, m), 5.11 (2H, s), 7.01 (1H, d, J=8.7 Hz), 7.27-7.51 (3H, m), 7.71-8.02 (5H, m), 11.00-13.00 (3H, m); NMR (32) (DMSO-d₆) δppm: 1.45-1.89 (2H, m), 2.00-2.38 (6H, m), 2.55-2.86 (6H, m), 3.01-3.22 (1H, m), 3.22-3.94 (9H, m), 3.77 (3H, s), 3.99-4.50 (3H, m), 4.50-4.70 (1H, m), 7.07-7.20 (1H, m), 7.20-7.37 (1H, m), 7.37-7.54 (3H, m), 7.67-7.89 (3H, m), 7.89-8.03 (1H, m), 11.06-12.62 (3H, m); NMR (33) (DMSO-d₆) δppm: 1.40-1.92 (2H, m), 1.92-2.30 (4H, m), 2.31 (3H, s), 2.55-2.90 (4H, m), 2.90-4.03 (10H, m), 4.03-4.34 (1H, m), 4.44-4.73 (1H, m), 5.11 (2H, s), 7.23 (1H, d, J=9.3H), 7.31 (1H, t, J=6.9 Hz), 7.32-7.48 (2H, m), 7.74-7.86 (2H, m), 7.86-8.05 (3H, m), 10.88-12.00 (2H, m), 12.70 (1H, br); NMR (34) (DMSO-d₆) δppm: 1.48-1.94 (2H, m), 2.00-2.39 (4H, m), 2.57-2.85 (4H, m), 2.85-4.03 (10H, m), 4.10-4.39 (1H, m), 4.48-4.71 (1H, m), 5.29 (2H, s), 7.21-7.57 (4H, m), 7.75-7.83 (2H, m), 7.98 (1H, d, J=7.4 Hz), 8.23 (1H, s), 8.32 (1H, d, J=8.7 Hz), 10.89-12.06 (2H, m), 12.76 (1H, br); NMR (35) (DMSO-d₆) δppm: 2.88-3.28 (4H, m), 3.73-4.31 (4H, m), 5.30 (2H, s), 7.31 (1H, t, J=6.9 Hz), 7.35-7.48 (3H, m), 7.75-7.85 (2H, m), 7.97 (1H, d, J=7.1 Hz), 8.23 (1H, s), 8.33 (1H, d, J=8.7 Hz), 9.37 (2H, br), 12.78 (1H, br); NMR (36) (DMSO-d₆) δppm: 1.2-1.5 (2H, m), 1.6-1.85 (8H, m), 2.31 (3H, s), 2.5-3.15 (15H, m), 3.9-4.0 (1H,), 4.4-4.5 (1H, m), 5.04 (2H, s), 6.81 (1H, d, J=8.5 Hz), 7.20 (1H, d, J=15.5 Hz), 7.25-7.5 (3H, m), 7.55 (1H, d, J=8.5 Hz), 7.75 (1H, d, J=7.5 Hz), 7.97 (1H, d, J=7 Hz); NMR (37) (DMSO-d₆) δppm: 1.4-1.9 (2H, m), 2.12 (6H, s), 2.0-4.0 (19H, m), 4.45-4.6 (1H, m), 4.95 (2H, s), 6.77 (2H, s), 6.88 (1H, d, J=16 Hz), 7.03 (1H, d, J=16 Hz), 7.35-7.5 (2H, m), 7.76 (1H, d, J=7.5 Hz), 7.99 (1H, d, J=8 Hz), 11.24, 12.04 (all 1H, br), 11.74 (1H, br), 12.64 (1H, br); NMR (38) (DMSO-d₆) δppm: 2.54-2.93 (5H, m), 2.93-3.78 (10H, m), 3.78-4.17 (7H, m), 4.17-4.44 (1H, m), 5.07 (2H, s), 6.65-6.78 (1H, m), 6.78-6.90 (1H, m), 7.18-7.71 (5H, m), 7.76 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7.1 Hz), 11.28 (2H, br), 12.68 (1H, br); NMR (39) (DMSO-d₆) δppm: 2.22 (3H, s), 2.33 (3H, s), 2.36 (3H, s), 2.80 (3H, d, J=4 Hz), 2.9-3.6 (6H, m), 4.15-4.3 (1H, m), 4.4-4.55 (1H, m), 5.06 (2H, s), 6.85 (1H, d, J=9 Hz), 7.24 (1H, d, J=15.5 Hz), 7.37 (1H, d, J=15.5 Hz), 7.25-7.55 (3H, m), 7.76 (1H, d, J=7 Hz), 7.98 (1H, d, J=7 Hz), 9.76 (1H, br), 12.60 (1H, br); NMR (40) (DMSO-d₆) δppm: 2.05-2.35 (2H, m), 2.54-2.98 (5H, m), 2.98-3.85 (10H, m), 3.85-4.19 (7H, m), 4.19-4.47 (1H, m),5.07 (2H, s), 6.65-6.79 (1H, m), 6.79-6.90 (1H, m), 7.18-7.71 (5H, m), 7.77 (1H, d, J=7.7 Hz), 8.00 (1H, d, J=7.8 Hz), 11.22 (2H, br), 12.68 (1H, br); NMR (41) (DMSO-d₆) δppm: 1.89-2.44 (4H, m), 2.53-3.78 (16H, m), 3.78-4.13 (6H, m), 4.13-4.42 (1H, m), 5.07 (2H, s), 6.70 (1H, dd, J=2.2 Hz, J=8.7 Hz). 6.81 (1H, d, J=2.2 Hz), 7.19-7.73 (5H, m), 7.76 (1H, d, J=7.8 Hz), 7.98 (1H, d, J=7.0 Hz), 10.61 (1H, br), 11.27 (1H, br), 12.71 (1H, br); NMR (42) (DMSO-d₆) δppm: 1.30 (6H, d, J=5.9 Hz), 2.55-4.19 (19H, m), 4.19-4.41 (1H, m), 4.82 (1H, sept, J=5.9 Hz), 5.07 (2H, s), 6.60-6.71 (1H, m), 6.76-6.79 (1H, m), 7.22-7.49 (3H, m), 7.64 (1H, d, J=8.7 Hz), 7.71-7.90 (2H, m), 7.98 (1H, d, J=7.1 Hz), 11.81 (2H, br), 12.58 (1H, br); NMR (43) DMSO-d₆) δppm: 1.35 (3H, d, J=6 Hz), 1.5-2.2 (4H, m),2.5-3.8 (13H, m), 3.88 (3H, s), 4.1-4.3 (1H, m), 4.45-4.65 (1H, m), 5.06 (2H, s), 6.70 (1H, d, J=9 Hz), 6.81 (1H, s), 7.27 (1H, d, J=15.5 Hz), 7.25-7.5 (2H, m), 7.56 (1H, d, J=15.5 Hz), 7.64 (1H, d, J=8.5 Hz), 7.77 (1H, d, J=8 Hz), 7.99 (1H, d, J=8 Hz), 12.5-13 (3H, br); NMR (44) (DMSO-d₆) δppm: 1.30 (3H, d, J=6.5 Hz), 1.5-2.3 (4H, m), 2.55-2.8 (1H, m), 3.0-4.7 (13H, m), 3.88 (3H, s), 5.07 (2H, s), 6.70 (1H, d, J=9 Hz), 6.81 (1H, m), 7.27 (1H, d, J=15.5 Hz), 7.25-7.5 (2H, m), 7.56 (1H, d, J=15.5 Hz), 7.64 (1H, d, J=8.5 Hz), 7.77 (1H, d, J=8 Hz), 7.98 (1H, d, J=7.5 Hz), 9.85 (1H, br), 10.01 (1H, br), 12.25 (1H, br); NMR (45) (DMSO-d₆) δppm: 2.05-2.20 (2H, m), 2.5-4.0 (18H, m), 3.88 (3H, s), 4.1-4.25 (1H, m), 4.5-4.65 (1H, m), 5.06 (2H, s), 6.70 (1H, d, J=8.5 Hz), 6.81 (1H, m), 7.28 (1H, d, J=15 Hz), 7.25-7.5 (2H, m), 7.56 (1H, d, J=15 Hz), 7.64 (1H, d, J=8.5 Hz), 7.77 (1H, d, J=8 Hz), 7.99 (1H, d, J=7.5 Hz), 10.78 (1H, br), 11.94 (1H, br), 12.66 (1H, br); NMR (46) (DMSO-d₆) δppm: 1.43-1.85 (2H, m), 1.97-2.42(4H, m), 2.58-2.82 (1H, m), 2.82-4.08 (18H, m), 4.08-4.30 (1H, m), 4.42-4.72 (1H, m), 5.06 (2H, s), 5.22-5.68 (2H, m), 6.62-6.78 (1H, m), 6.78-6.95(1H, m), 7.24-7.70 (5H, m), 7.77 (1H, d, J=6.2 Hz), 7.99 (1H, d, J=5.8 Hz), 10.35 (2H, br), 11.48 (1H, br); NMR (47) DMSO-d₆) δppm: 1.3-2.0 (6H, m), 2.37 (6H, s), 2.8-4.2 (16H, m), 3.88 (3H, s), 5.07 (2H, s), 6.71 (1H, dd, J=7H, J=2 Hz), 6.81 (1H, d, J=2 Hz), 7.25 (1H, d, J=15 Hz), 7.25-7.5 (3H, m), 7.65-7.75 (2H, m), 7.77 (1H, d, J=7 Hz), 7.98 (1H, d, J=6 Hz), 9.40 (1H, br); NMR (48) DMSO-d₆) δppm: 2.4-4.5(23H, m), 3.88 (3H, s), 5.09 (2H, s), 6.71 (1H, d, J=9 Hz), 6.82 (1H, s), 7.2-7.75 (5H, m), 7.77 (1H, d, J=8 Hz), 7.98 (1H, d, J=7 Hz), 10.98 (1H, br), 11.58 (1H, br), 12.71 (1H, br); NMR (49) DMSO-d₆) δppm: 2.16 (3H, s), 2.23 (3H, s), 2.74 (3H, d, J=4 Hz), 2.85-3.7 (6H, m), 3.86 (3H, s), 4.15-4.6 (2H, m), 4.95 (2H, s), 6.66 (1H, d J=8.5 Hz), 6.79 (1H, m), 7.27 (1H, d, J=15 Hz), 7.61 (1H, d, J=15 Hz), 7.63 (1H, d, J=8.5 Hz), 11.42 (1H, br); NMR (50) DMSO-d₆) δppm: 1.39-1.90 (2H, m), 1.98-2.37 (4H, m), 2.58-2.90 (4H, m), 2.98-3.99 (10H, m), 4.11-4.32 (1H, m), 4.48-4.70 (1H, m), 5.09 (2H, s), 6.93-7.15 (2H, m), 7.20-7.62 (4H, m), 7.80-7.92 (2H, m), 7.99 (1H, d, J=7.3 Hz), 10.80-11.95 (2H, m), 12.68 (1H, br); NMR (51) (DMSO-d₆) δppm: 1.67-2.03 (2H, m), 2.80 (3H, s), 2.99-4.35 (20H, m), 5.07 (2H, s), 6.70 (1H, dd, J=2.2 Hz, J=8.7 Hz), 6.82 (1H, d, J=2.2 Hz), 7.19-7.74 (5H, m), 7.77 (1H, d, J=7.5 Hz), 7.99 (1H, d, J=7.9 Hz), 10.80-12.32 (2H, br), 12.69 (1H, br); NMR (52) (DMSO-d₆) δppm: 2.15 (3H, s), 2.22 (3H, s), 2.83 (3H, s), 2.5-4.4 (17H, m), 3.86 (3H, s), 4.94 (2H, s), 6.65 (1H, d, J=8.5 Hz), 6.78 (1H, s), 7.2-7.7 (3H, m), 12.05 (1H, br); NMR (53) (DMSO-d₆) δppm: 2.36 (6H, s), 2.55-4.45 (20H, m), 4.92 (2H, q, J=8.9 Hz), 5.08 (2H, s), 6.80 (1H, dd, J=2.3 Hz, J=8.9 Hz), 6.94 (1H, d, J=2.3 Hz), 7.21-7.75 (5H, m), 7.77 (1H, d, J=8.1 Hz), 7.98 (1H, d, J=7.1 Hz), 9.95 (2H, br), 12.63 (1H, br); NMR (54) (DMSO-d₆) δppm: 1.40 (6H, d, J=6.0 Hz), 1.51-1.86 (2H, m), 2.05-2.30 (2H, m), 2.57-2.73 (1H, m), 2.79 (3H, s), 2.98-3.87 (8H, m), 3.88 (3H, s), 4.14-4.25 (1H, m), 4.40-4.70 (1H, m), 5.06 (2H, s), 6.70 (1H, dd, J=2.2 Hz, J=8.8 Hz), 6.81 (1H, d, J=2.2 Hz), 7.23-7.66 (5H, m), 7.77 (1H, d, J=7.6 Hz), 8.00 (1H, d, J=7.0 Hz), 11.40-13.10 (3H, m); NMR (55) (DMSO-d₆) δppm: 1.4-2.4 (4H, m), 2.34 (3H, s), 2.7-5.0 (9H, m), 3.88 (3H, s), 5.06 (2H, s), 6.71 (1H, dd, J=2 Hz, J=9 Hz), 6.82 (1H, d, J=2 Hz), 7.2-7.5 (3H, m), 7.55-7.8 (3H, m), 7.99 (1H, d, J=7 Hz), 9.6-10.2 (1H, m), 12.60 (1H, br); NMR (56) (DMSO-d₆) δppm: 1.40-1.84 (2H, m), 2.00-2.42 (4H, m), 2.67 (1H, t, J=12.5 Hz), 2.77 (3H, s), 3.12 (1H, t, J=12.5 Hz), 3.24-4.05 (12H, m), 4.10-4.31 (1H, m), 4.48-4.71 (1H, m), 5.07 (2H, s), 6.70 (1H, dd, J=2.1 Hz, J=8.7 Hz), 6.82 (1H, d, J=2.1 Hz), 7.19-7.62 (4H, m), 7.64 (1H, d, J=8.6 Hz), 7.77 (1H, d, J=8.1 Hz), 7.99 (1H, d, J=7.9 Hz), 11.05-12.10 (2H, m), 12.68 (1H, br).

Example 344

2-{3-Allyloxy-4-[3-(1-piperidinyl)carbonylacryloyl]phenoxymethylcarbonylamino}benzothiazole (0.55 g) is dissolved in methanol (70 ml) and dioxane (40 ml), and thereto are added 10% palladium-carbon (0.15 g), p-toluenesulfonic acid monohydrate (70 mg) and water (3 ml). The mixture is subjected to deaeration, and the mixture is refluxed under nitrogen atmosphere overnight. The mixture is filtered through a cerite pad, and to the filtrate is added water-methylene chloride, and the mixture is separated, and dried over sodium sulfate. The residue is crystallized from ethanol-methylene chloride, and recrystallized from dimethylformamide-ethanol to give 2-{3-hydroxy-4-[3-(1-piperidinyl)carbonylacryloyl]phenoxymethylcarbonylamino}benzothiazole (120 mg).

Yellow powder; M.p. 207.3-210° C.

Example 345

To a solution of dimethyl [{2-methoxy-4-[2-(2-benzothiazolylaminocarbonyl)ethyl]benzoyl}methyl]phosphonate (6.4 g) in tetrahydrofuran (100 ml) is added 40% glyoxylic acid (7.7 ml), and further thereto is added dropwise a 5% aqueous sodium hydroxide solution (70 ml) under ice-cooling. The mixture is stirred for 30 minutes, and the mixture is acidified with 5% hydrochloric acid. The precipitated yellow powder is collected by filtration, washed with ethanol, dried, and then recrystallized from dimethylformamide-ethanol to give 2-{2-[3-methoxy-4-(trans-3-carboxyacryloyl)phenyl]ethylcarbonyl amino}benzothiazole (4.0 g).

Yellow powder; M.p. 260-261° C.

Example 346

To tetrahydrofuran (50 ml) is added dimethyl[{2-dimethylamino-4-[(2-benzothiazolyl)aminocarbonylmethoxy]benzoyl}methyl]phosphonate (4.70 g), and thereto are added 5% aqueous sodium hydroxide solution (40 ml) and glyoxylic acid (3.5 ml) under ice-cooling, and the mixture is stirred at the same temperature for 10 minutes. After confirming that the starting compounds are consumed, the mixture is acidified with hydrochloric acid, and concentrated under reduced pressure to remove the solvent. The precipitated crystals are collected by filtration, dissolved in dimethylformamide (100 ml), and the mixture is heated with stirring at 100° C. for 30 minutes. After cooling, to the reaction solution is added isopropyl alcohol, and the precipitated crystals are collected by filtration. The crystals are recrystallized from dimethylformamide-isopropyl alcohol to give 1,1-dimethyl-2-carboxy-4-oxo-7-[(2-benzothiazolyl)aminocarbonylmethoxy]-1,2,3,4-tetrahydroquinolinium chloride (2.46 g).

Pale green powder; M.p. 184.5-186.5° C.

Using the suitable starting compounds, the compounds as listed in Table 150-160 are obtained in the same manner as in Example 1 or 5.

                                      TABLE 150                                    __________________________________________________________________________      ##STR965##                                                                    __________________________________________________________________________     Example 347                                                                    R.sup.5 : H         A: --CH.sub.2 CH.sub.2 --                                                               m: 1                                                                               s: 0                                            Z: -- R.sup.A : H R.sup.4 : H                                                Position of --COCH═CHCOOH: 4-position                                        M.p. 253.5-255° C. Crystalline form: White powder                       Solvent for recrystallization: Dimethylformamide-ethanol                       Form: Free                                                                   Example 348                                                                    R.sup.5 : --OCH.sub.3 (3-position)                                                                 A: --CH.sub.2 CH.sub.2 --                                                               m: 1                                                                               s: 0                                            Z: -- R.sup.A : H R.sup.4 : H                                                Position of --COCH═CHCOOH: 4-position                                        M.p. 260-261° C. Crystalline form: Yellow powder                        Solvent for recrystallization: Dimethylformamide-ethanol                       Form: Free                                                                   Example 349                                                                                                       A: R966##                                                                    --CH.sub.2 -- m: 1 s: 1                          - Z: O R.sup.A : H R.sup.4 : H                                              Position of --COCH═CHCOOH: 4-position                                        M.p. 184-186° C. Crystalline form: Pale yellow powder                   Solvent for recrystallization: Dimethylformamide-ethanol-water                 Form: HCl                                                                    __________________________________________________________________________

                  TABLE 151                                                        ______________________________________                                         Example 350                                                                      R.sup.5 : --OCH.sub.3 (3-position)                                                                     A:  --CH.sub.2 --                                                                       m: 1 s: 1                                   Z: O                  R.sup.A :   R.sup.4 : H                                     --N(CH.sub.3).sub.2                                                            (6-position)                                                                Position of --COCH═CHCOOH: 4-position                                        M.p. 263-264° C. (decomp.) Crystalline form: Pale brown powder         Solvent for recrystallization: Dimethylformamide-ethanol-water                 Form: Hydrate                                                                   Example 351                                                                                                            A:  967##                                                                    --CH.sub.2 -- m: 1 s: 1                   -                                                                           Z: O                  R.sup.A : H                                                                             R.sup.4 : H                                     Position of --COCH═CHCOOH: 4-position                                        M.p. 294-297° C. Crystalline form: Yellow powder                        Solvent for recrystallization: Dimethylformamide                               Form: Free                                                                     Example 352                                                                        R.sup.5 : --OCH.sub.2 CH═CH.sub.2 (3-position)                                                     A:     m: 1 s: 1                                    --CH.sub.2 --                                                               Z: O                  R.sup.A : H                                                                             R.sup.4 : H                                     Position of --COCH═CHCOOH: 4-position                                        M.p. 248-254° C. Crystalline form: Pale yellow powder                   Solvent for recrystallization: Diluted hydrochloric acid                       NMR (36) Form: Free                                                          ______________________________________                                    

                                      TABLE 152                                    __________________________________________________________________________      ##STR968##                                                                    __________________________________________________________________________     Example 353                                                                     ##STR969##         A: --CH.sub.2 -- m: 1 s: 1                                    -                                                                           Z: O     R.sup.4 : H                                                           Position of --COCH═CHCOOH: 4-position                                      M.p. 270.0-271.5° C.                                                                         Crystalline form: Pale yellow powder                      Solvent for recrystallization: Dimethylformamide-dichloromethane                 Form: Free                                                                   Example 354                                                                     ##STR970##         A: --CH.sub.2 -- m: 1 s: 1                                    -                                                                           Z: O     R.sup.4 : H                                                           Position of --COCH═CHCOOH: 4-position                                      M.p. 270.5-273.3° C.                                                                         Crystalline form: Yellow powder                           Solvent for recrystallization: Dimethylformamide-dichloromethane                 Form: Free                                                                   Example 355                                                                      R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (2-position) & --OCH.sub.3             (5-position)                                                                   A: --CH.sub.2 --                                                                             m: 2 s: 1    Z: O R.sup.4 : H                                    Position of --COCH═CHCOOH: 4-position                                      M.p. 203-206° C.                                                                             Crystalline form: Yellow powder                           Solvent for recrystallization: Dimethylformamide-dichloromethane                 Form: Free                                                                   __________________________________________________________________________

                  TABLE 153                                                        ______________________________________                                         Example 356                                                                      R.sup.5 : --(CH.sub.2).sub.2 CH.sub.3 (2-position) & --OCH.sub.3             (3-position)                                                                     A: --CH.sub.2 --                                                                           m: 2      s: 1   Z: O    R.sup.4 : H                             Position of --OCH═CHCOOH: 4-position                                         M.p. 232-234° C.                                                                          Crystalline form: Yellow powder                            Solvent for recrystallization: Tetrahydrofuran-water                             Form: Free                                                                     Example 357                                                                   # A: 971##                                                                      --CH.sub.2 -- m: 1 s: 1                                                         -                                                                           Z: O      R.sup.4 : H                                                          Position of --COCH═CHCOOH: 4-position                                        M.p. 237-245° C. (decomp.)                                                                Crystalline form: White powder                             Solvent for recrystallization: Tetrahydrofuran-water                             NMR (37)    Form: Free                                                       Example 358                                                                      R.sup.5 : --CH.sub.2 CH.sub.3 (2-position) & --OCH.sub.3 (5-position)          A: --CH.sub.2 --                                                                           m: 2      s: 1   Z: O    R.sup.4 : H                             Position of --COCH═CHCOOH: 4-position                                        M.p. 127-138° C. (decomp.)                                                                Crystalline form: Yellow powder                            Solvent for recrystallization: Dimethylformamide-acetonitrile                    NMR (38)    Form: Free                                                       ______________________________________                                    

                  TABLE 154                                                        ______________________________________                                         Example 359                                                                      R.sup.5 : --OCH.sub.3 (2- & 6-positions)                                       A: --CH.sub.2 --                                                               m: 2                                                                           s: 1                                                                           Z: O                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 4-position                                      M.p. 137-138° C.                                                        Crystalline form: Yellow powder                                                Solvent for recrystallization: Dimethylformamide-ethanol-diethyl              ether-n-hexane                                                                 Form: Free                                                                     Example 360                                                                    R.sup.5 : --OCH.sub.3 (2- & 3-positions)                                       A: --CH.sub.2 --                                                               m: 2                                                                           s: 1                                                                           Z: O                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 4-position                                      M.p. 235-237° C.                                                        Crystalline form: Yellow powder                                                Solvent for recrystallization: Dichloromethane-dimethylformamide               Form: Free                                                                     Example 361                                                                    R.sup.5 : --CH.sub.3 (2-position) & --OCH.sub.3 (3-position)                   A: --CH.sub.2 --                                                               m: 2                                                                           s: 1                                                                           Z: O                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 4-position                                      Crystalline form: Pale yellow powder                                           NMR (39)                                                                       Form: Free                                                                     Example 362                                                                    R.sup.5 : --CH.sub.3 (2-position) & --OCH.sub.3 (3-position)                   A: --CH.sub.2 --                                                               m: 2                                                                           s: 1                                                                           Z: O                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 6-position                                      Crystalline form: Pale brown powder                                            NMR (40)                                                                       Form: Free                                                                    ______________________________________                                    

                  TABLE 155                                                        ______________________________________                                         Example 363                                                                     R.sup.5 : --(CH.sub.2).sub.3 CH.sub.3 (2-position) & --OCH.sub.3              (3-position)                                                                     A: --CH.sub.2 --                                                               m: 2                                                                           s: 1                                                                           Z: O                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 4-position                                      Crystalline form: Yellow powder                                                NMR (41)                                                                       Form: Free                                                                     Example 364                                                                    R.sup.5 : --SCH.sub.3 (3-position)                                             A: --CH.sub.2 --                                                               m: 1                                                                           s: 1                                                                           Z: O                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 4-position                                      Crystalline form: Yellow powder                                                NMR (42)                                                                       Form: Free                                                                     Example 365                                                                    R.sup.5 : --CH.sub.2 CH.sub.3 (2-position) & --OCH.sub.3 (3-position)         A: --CH.sub.2 --                                                               m: 2                                                                           s: 1                                                                           Z: O                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 4-position                                      Crystalline form: Pale brown powder                                            NMR (43)                                                                       Form: Free                                                                     Example 366                                                                    R.sup.5 : --OCH.sub.3 (3-position)                                             A: --CH(CH.sub.3)--                                                            m: 1                                                                           s: 1                                                                           Z: O                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 4-position                                      M.p. 225-228° C. (decomp.)                                              Crystalline form: Pale brown powder                                            Solvent for recrystallization: Dimethylformamide-ethanol-diethyl               ether-water                                                                    Form: Free                                                                    ______________________________________                                    

                  TABLE 156                                                        ______________________________________                                         Example 367                                                                      #STR972##                                                                      -                                                                            A: --CH.sub.2 --                                                                          m: 2     s: 1      Z: O   R.sup.4 : H                               Position of --COCH═CHCOOH: 4-position                                        M.p. 255-256° C. (decomp.)                                                                Crystalline form: Yellow powder                            Solvent for recrystallization: Dimethylformamide-acetonitrile Form: Free        Example 368                                                                    R.sup.5 : --OCH.sub.3 (3-position)                                              A: --(CH.sub.2).sub.3 --                                                                    m: 1     s: 1    Z: O   R.sup.4 : H                             Position of --COCH═CHCOOH: 4-position                                        M.p. 239-241° C. (decomp.)                                                                Crystalline form: Pale yellow powder                       Solvent for recrystallization: Dimethylformamide-acetonitrile Form: Free        Example 369                                                                    R.sup.5 : --(CH.sub.2).sub.2 CH.sub.3 (2-position) & --OCH.sub.3              (5-position)                                                                     A: --CH.sub.2 --                                                                            m: 2     s: 1    Z: 0   R.sup.4 : H                             Position of --COCH═CHCOOH: 4-position                                        M.p. 222-224° C. (decomp.)                                                                Crystalline form: Pale yellow powder                       Solvent for recrystallization: Dimethylformamide-acetonitrile Form: Free        Example 370                                                                    R.sup.5 : --CH.sub.2 CH═CH.sub.2 (2-position) & --OCH.sub.3 (5-positi     on)                                                                              A: --CH.sub.2 --                                                                            m: 2     s: 1    Z: O   R.sup.4 : H                             Position of --COCH═CHCOOH: 4-position                                        M.p. 224-225° C. (decomp.)                                                                Crystalline form: Yellow powder                            Solvent for recrystallization: Dimethylformamide-acetonitrile Form:            ______________________________________                                         Free                                                                      

                                      TABLE 157                                    __________________________________________________________________________      ##STR973##                                                                    __________________________________________________________________________     Example 371                                                                      R.sup.5 : --OCH.sub.3 (2- & 5-positions)                                     A: --CH.sub.2 --                                                                        m: 2 R.sup.4 : H                                                      Position of --COCH═CHCOOH: 4-position                                      NMR (44) Crystalline form: Yellow powder                                                                  Form: Free                                            Example 372                                                                  R.sup.5 : --CH.sub.3 (2-position) & --OCH.sub.3 (5-position)                   A: --CH.sub.2 --                                                                        m: 2 R.sup.4 : H                                                      Position of --COCH═CHCOOH: 4-position                                      NMR (45) Crystalline form: Yellow powder                                         Example 373                                                                  R.sup.5 : --OC.sub.2 H.sub.5 (2-position) & --OCH.sub.3 (5-position)           A: --CH.sub.2 --                                                                        m: 2 R.sup.4 : H                                                      Position of --COCH═CHCOOH: 4-position                                      M.p. 202-204° C. (decomp.)                                                            Crystalline form: Yellow powder                                  Solvent for recrystallization: Dimethylformamide-acetonitrile                                                 Form: Free                                      __________________________________________________________________________

                  TABLE 158                                                        ______________________________________                                         Example 374                                                                      R.sup.5 : --Br (2-position) & --OCH.sub.3 (5-position)                         A: --CH.sub.2 --                                                               m: 2                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 4-position                                      M.p. 238-239° C. (decomp.)                                              Crystalline form: Yellow powder                                                Solvent for recrystallization: Dimethylformamide-acetonitrile                  Form: Free                                                                     Example 375                                                                    R.sup.5 : --CH(CH.sub.3).sub.2 (2-position) & --OCH.sub.3 (5-position)        A: --CH.sub.2 --                                                               m: 2                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 4-position                                      NMR (46)                                                                       Crystalline form: Yellow powder                                                Form: Free                                                                     Example 376                                                                    R.sup.5 : --(CH.sub.2).sub.5 CH.sub.3 (2-position) & --OCH.sub.3              (5-position)                                                                     A: --CH.sub.2 --                                                               m: 2                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 4-position                                      NMR (47)                                                                       Crystalline form: Yellow powder                                                Form: Free                                                                     Example 377                                                                    R.sup.5 : --N(CH.sub.3).sub.2 (2-position)                                     A: --CH.sub.2 --                                                               m: 1                                                                           R.sup.4 : H                                                                    Position of --COCH═CHCOOH: 4-position                                      NMR (48)                                                                       Crystalline form: Pale yellow powder                                           Form: Free                                                                   ______________________________________                                    

                                      TABLE 159                                    __________________________________________________________________________      ##STR974##                                                                    __________________________________________________________________________     Example 378                                                                      R.sup.5 : --OCH.sub.3 (3-position)                                           A: --CH.sub.2 --                                                                        m: 1  R.sup.4 : H                                                                           T: --CH.sub.2 --                                                                        u: 1                                            Position of --COCH═CHCOOH: 4-position                                      NMR (49)   Crystalline form: Yellow powder                                                                    Form: Free                                      __________________________________________________________________________

                  TABLE 160                                                        ______________________________________                                          ##STR975##                                                                    ______________________________________                                         Example 379                                                                      R.sup.4 : H                                                                                                      #STR976##                                     -                                                                           M.p. 211.5-213° C.                                                                  Crystalline form: White powder                                                                   Form: Free                                       Solvent for recrystallization: Dimethylformamide-methanol                      ______________________________________                                    

Using the suitable starting compounds, the compounds as listed in Tables 161-193 are obtained in the same manner as in Example 3 or 4.

                                      TABLE 161                                    __________________________________________________________________________      ##STR977##                                                                    __________________________________________________________________________     Example 380                                                                     ##STR97 R#                                                                            .sup.4 : H                                                                      ##S R979##                                                               -                                                                           M.p. 187.5-188.5° C.                                                                  Crystalline form: White powder                                   Solvent for recrystallization: Ethanol-diethyl ether                                                    Form: Free                                            Example 381                                                                     ##STR98 R#                                                                            .sup.4 : H                                                                -                                                                             #STR981##                                                                       -                                                                           M.p. 164-166° C.                                                                      Crystalline form: white powder                                   Solvent for recrystallization: Ethanol-diethyl ether                                                    Form: 2HCl                                            __________________________________________________________________________

                                      TABLE 162                                    __________________________________________________________________________     Example 382                                                                     ##STR982##                                                                                   #STR983##                                                          -                                                                           R.sup.4 : H                                                                               M.p. 148.4-151.2° C.                                                                           Crystalline form: Yellow powder              Solvent for recrystallization: Ethanol-diethyl ether                                                                    Form: 2HCl                            Example 383                                                                     ##STR984##                                                                                   #STR985##                                                          -                                                                           R.sup.4 : H                                                                               M.p. 200-210° C. (decomp.)                                                                     Crystalline form: Pale brown powder          Solvent for recrystallization: Ethanol-water-diethyl ether                                                              Form: 2HCl--H.sub.2 O                   NMR (1)                                                                      Example 384                                                                     ##STR986##                                                                                   #STR987##                                                          -                                                                           R.sup.4 : H                                                                               M.p. 160.2-162.3° C.                                                                           Crystalline form: Pale yellow powder         Solvent for recrystallization: Ethanol-diethyl ether                                                                    Form: 2HCl                            __________________________________________________________________________

                                      TABLE 163                                    __________________________________________________________________________     Example 385                                                                     ##STR988##                                                                                   #STR989##                                                          -                                                                           R.sup.4 : H                                                                               M.p. 156-166° C. (decomp.)                                                                     Crystalline form: Pale brown powder          Solvent for recrystallization: Ethanol-water-diethyl ether                                                              Form: 3HCl--3H.sub.2 O                  NMR (2)                                                                      Example 386                                                                     ##STR990##                                                                                   #STR991##                                                          -                                                                           R.sup.4 : H                                                                               M.p. 178-179° C.                                                                               Crystalline form: Pale yellow powder         Solvent for recrystallization: Ethanol   Form: Free                            Example 387                                                                     ##STR992##                                                                                   #STR993##                                                          -                                                                           R.sup.4 : H                                                                               M.p. 252-253.5° C.                                                                             Crystalline form: White powder               Solvent for recrystallization: Ethanol-water-diethyl ether                                                              Form: Free                            __________________________________________________________________________

                                      TABLE 164                                    __________________________________________________________________________     Example 388                                                                     ##STR994##                                                                                  #STR995##                                                           -                                                                           R.sup.4 : H                                                                              M.p. 244-246° C. (decomp.)                                                                     Crystalline form: Pale brown powder           Solvent for recrystallization: Ethanol-chloroform                                                                         Form: Free                          Example 389                                                                     ##STR996##                                                                                  #STR997##                                                           -                                                                           R.sup.4 : H                                                                              M.p. 173-176° C.                                                                               Crystalline form: Pale yellow powder          Solvent for recrystallization: Ethanol-water-diethyl ether                                                                Form: 2HCl                          Example 390                                                                     ##STR998##                                                                                  #STR999##                                                           -                                                                           R.sup.4 : H                                                                              M.p. 161.2-163.0° C.                                                                           Crystalline form: Pale yellow powder          Solvent for recrystallization: Ethanol-water-diethyl ether                                                                Form: 2HCl                          __________________________________________________________________________

                                      TABLE 165                                    __________________________________________________________________________     Example 391                                                                     ##STR10 0##                                                                             #STR1001##                                                              -                                                                           R.sup.4 : H                                                                               M.p. 172-176° C.                                                                          Crystalline form: White powder                    Solvent for recrystallization: Ethanol-water-diethyl ether                                                      Form: Free                                    Example 392                                                                     ##STR10 2##                                                                             #STR1003##                                                              -                                                                           R.sup.4 : H                                                                               M.p. 234.5-236 5° C.                                                                      Crystalline form: Yellow powder                   Solvent for recrystallization: Ethanol-water                                                                Form: Methanesulfonate                            Example 393                                                                     ##STR10 4##                                                                             #STR1005##                                                              -                                                                           R.sup.4 : H                                                                               M.p. 114-117° C.                                                                          Crystalline form: Pale yellow powder              Solvent for recrystallization: Ethanol-diethyl ether                                                        Form: Dimethanesulfonate                          __________________________________________________________________________

                                      TABLE 166                                    __________________________________________________________________________     Example 394                                                                     ##STR10 6##                                                                             #STR1007##                                                              -                                                                           R.sup.4 : H M.p. 167.0-168.5° C.                                                                      Crystalline form: Pale yellow powder             Solvent for recrystallization: Ethanol-water                                                                     Form: 2HCl                                   Example 395                                                                     ##STR10 8##                                                                             #STR1009##                                                              -                                                                           R.sup.4 : H M.p. 183-183.5° C.                                                                        Crystalline form: Pale brown powder              Solvent for recrystallization: Ethanol                                                                           Form: Free                                   Example 396                                                                     ##STR10 0##                                                                             #STR1011##                                                              -                                                                           R.sup.4 : H M.p. 237.5-238.5° C.                                                                      Crystalline form: Yellow powder                  Solvent for recrystallization: Ethanol-water                                                                     Form: 2HCl                                   __________________________________________________________________________

                                      TABLE 167                                    __________________________________________________________________________     Example 397                                                                     ##STR10 2##                                                                             #STR1013##                                                              -                                                                           R.sup.4 : H M.p. 158.0-161.0° C.                                                                      Crystalline form: Yellow powder                  Solvent for recrystallization: Ethanol-water                                                                     Form: 2HCl                                   Example 398                                                                     ##STR10 4##                                                                             #STR1015##                                                              -                                                                           R.sup.4 : H M.p. 162.0-164.3° C.                                                                      Crystalline form: Pale yellow powder             Solvent for recrystallization: Ethanol-water                                                                     Form: 2HCl                                   Example 399                                                                     ##STR10 6##                                                                             #STR1017##                                                              -                                                                           R.sup.4 : H M.p. 133-136° C.                                                                          Crystalline form: Yellow powder                  Solvent for recrystallization: Ethanol-water                                                                     Form: Methanesulfonate                       __________________________________________________________________________

                                      TABLE 168                                    __________________________________________________________________________     Example 400                                                                     ##STR10 8##                                                                             #STR1019##                                                              -                                                                           R.sup.4 : H M.p. 207.3-210.0° C.                                                                      Crystalline form: Yellow powder                  Solvent for recrystallization: Dimethylformamide-ethanol                                                         Form: Free                                   Example 401                                                                     ##STR10 0##                                                                             #STR1021##                                                              -                                                                           R.sup.4 : H M.p. 220-240° C. (decomp.)                                                                Crystalline form: Pale yellow powder             Solvent for recrystallization: Ethanol-diethyl ether                                                             Form: 2HCl                                     NMR (3)                                                                      Example 402                                                                     ##STR10 2##                                                                             #STR1023##                                                              -                                                                           R.sup.4 : H M.p. 170-180° C. (decomp.)                                                                Crystalline form: Pale yellow powder             Solvent for recrystallization: Ethanol-diethyl ether                                                             Form: HCl                                      NMR (4)                                                                      __________________________________________________________________________

                                      TABLE 169                                    __________________________________________________________________________     Example 403                                                                     ##STR10 4##                                                                             #STR1025##                                                              -                                                                           R.sup.4 : H                                                                             M.p. 190-220° C. (decomp.)                                                                 Crystalline form: Pale orange powder               Solvent for recrystallization: Ethanol-diethyl ether                                                             Form: 2HCl                                     NMR (5)                                                                      Example 404                                                                     ##STR10 6##                                                                             #STR1027##                                                              -                                                                           R.sup.4 : H                                                                             M.p. 138.5-140.3° C.                                                                       Crystalline form: Yellow powder                    Solvent for recrystallization: Ethanol-water-diethyl ether                       Form: Methanesulfonate                                                       Example 405                                                                     ##STR10 8##                                                                             #STR1029##                                                              -                                                                           R.sup.4 : H                                                                             M.p. 217.4-219.0° C.                                                                       Crystalline form: Yellow powder                    Solvent for recrystallization: Ethanol-diethyl ether-dichloromethane            Form: Methanesulfonate                                                        __________________________________________________________________________

                                      TABLE 170                                    __________________________________________________________________________     Example 406                                                                     ##STR10 0##                                                                             #STR1031##                                                              -                                                                           R.sup.4 : H M.p. 138.2-139.5° C.                                                                      Crystalline form: Pale yellow powder             Solvent for recrystallization: Ethanol-water-diethyl ether                       Form: Methanesulfonate                                                       Example 407                                                                     ##STR10 2##                                                                             #STR1033##                                                              -                                                                           R.sup.4 : H M.p. 168.5-171.0° C.                                                                      Crystalline form: Yellow powder                  Solvent for recrystallization: Ethanol-water-diethyl ether                                                       Form: 2HCl                                   Example 408                                                                     ##STR10 4##                                                                             #STR1035##                                                              -                                                                           R.sup.4 : H M.p. 132-134° C.                                                                          Crystalline form: White powder                   Solvent for recrystallization: Ethanol-diethyl ether                             Form: Methanesulfonate                                                       __________________________________________________________________________

                                      TABLE 171                                    __________________________________________________________________________     Example 409                                                                     ##STR10 6##                                                                             #STR1037##                                                              -                                                                           R.sup.4 : H M.p. 190-193° C.                                                                          Crystalline form: Yellow powder                  Solvent for recrystallization: Ethanol-acetone-diethyl ether                     Form: 2HCl                                                                   Example 410                                                                     ##STR10 8##                                                                             #STR1039##                                                              -                                                                           R.sup.4 : H M.p. 110-150° C. (decomp.)                                                                Crystalline form: Pale yellow powder             Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether           Form: Dimethanesulfonate                                                                        NMR (6)                                                       Example 411                                                                     ##STR10 0##                                                                             #STR1041##                                                              -                                                                           R.sup.4 : H M.p. 190-240° C. (decomp.)                                                                Crystalline form: Pale yellow powder             Solvent for recrystallization: Ethanol-diethyl ether                           Form: 2HCl    NMR (7)                                                          __________________________________________________________________________

                                      TABLE 172                                    __________________________________________________________________________     Example 412                                                                              #STR1042##                                                                     #STR1043##                                                           R.sup.4 : H M.p. 190-210° C. (decomp.) Crystalline form: Pale           yellow powder                                                                    Solvent for recrystallization: Ethanol-diethyl ether                           Form: 2HCl NMR (8)                                                           Example 413                                                                              #STR1044##                                                                     #STR1045##                                                           R.sup.4 : H M.p. 167.0-169.0° C. Crystalline form: Yellow powder         Solvent for recrystallization: Ethanol Form: 2HCl                             Example 414                                                                              #STR1046##                                                                     #STR1047##                                                           R.sup.4 : H M.p. 200-220° C. (decomp.) Crystalline form: Pale           yellow powder                                                                    Solvent for recrystallization: Ethanol-water-diethyl ether                     Form: 2HCl NMR (9)                                                           __________________________________________________________________________

                                      TABLE 173                                    __________________________________________________________________________     Example 415                                                                              #STR1048##                                                                     #STR1049##                                                           R.sup.4 : H M.p. 177-180° C. Crystalline form: Yellow powder             Solvent for recrystallization: Dichloromethane-diisopropyl ether               Form: 2HCl                                                                    Example 416                                                                              #STR1050##                                                                     #STR1051##                                                           R.sup.4 : H M.p. 179-182° C. Crystalline form: Yellow powder             Solvent for recrystallization: Dichloromethane-diisopropyl ether               Form: 2HCl                                                                    Example 417                                                                              #STR1052##                                                                     #STR1053##                                                           R.sup.4 : H M.p. 158-159° C. Crystalline form: Yellow powder             Solvent for recrystallization: Dichloromethane-diisopropyl ether               Form: 2HCl                                                                    __________________________________________________________________________

                                      TABLE 174                                    __________________________________________________________________________     Example 418                                                                              #STR1054##                                                                     #STR1055##                                                           R.sup.4 : H M.p. 230-232° C. Crystalline form: Yellow powder             Solvent for recrystallization: Methanol-diethyl ether                          Form: 2HCl                                                                    Example 419                                                                              #STR1056##                                                                     #STR1057##                                                           R.sup.4 : M.p. 221-224° C. Crystalline form: Yellow powder               Solvent for recrystallization: Methanol-diethyl ether                          Form: 2HCl                                                                    Example 420                                                                              #STR1058##                                                                     #STR1059##                                                           R.sup.4 : H M.p. 179-182° C. Crystalline form: Yellow powder             Solvent for recrystallization: Methanol-diethyl ether                          Form: 2HCl                                                                    __________________________________________________________________________

                                      TABLE 175                                    __________________________________________________________________________     Example 421                                                                              #STR1060##                                                                     #STR1061##                                                           R.sup.4 : H M.p. 146.2-148.5° C. Crystalline form: Gray powder           Solvent for recrystallization: Ethanol                                         Form: HCl                                                                     Example 422                                                                              #STR1062##                                                                     #STR1063##                                                           R.sup.4 : H M.p. 153-155° C. Crystalline form: Yellow powder             Solvent for recrystallization: Dichloromethane Form: 2HCl                     Example 423                                                                              #STR1064##                                                                     #STR1065##                                                           R.sup.4 : H M.p. 225-228° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol Form: Methanesulfonate                 __________________________________________________________________________

                                      TABLE 176                                    __________________________________________________________________________     Example 424                                                                              #STR1066##                                                                     #STR1067##                                                           R.sup.4 : H NMR (10) Crystalline form: Pale yellow amorphous                     Form: Methanesulfonate                                                       Example 425                                                                              #STR1068##                                                                     #STR1069##                                                           R.sup.4 : H M.p. 140-143° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol Form: Methanesulfonate                 Example 426                                                                              #STR1070##                                                                     #STR1071##                                                           R.sup.4 : H M.p. 152.4-154.8° C. Crystalline form: Pale yellow          powder                                                                           Solvent for recrystallization: Acetone-dichloromethane-water                   Form: 2HCl                                                                   __________________________________________________________________________

                                      TABLE 177                                    __________________________________________________________________________     Example 427                                                                              #STR1072##                                                                     #STR1073##                                                           R.sup.4 : H M.p. 154-155° C. Crystalline form: Yellow powder             Solvent for recrystallization: Ethanol-diethyl ether Form: Methanesulfona     te                                                                             Example 428                                                                              #STR1074##                                                                     #STR1075##                                                           R.sup.4 : H M.p. 165-168° C. Crystalline form: Yellow powder             Solvent for recrystallization: Dichloromethane-diethyl ether                   Form: Methanesulfonate                                                        Example 429                                                                              #STR1076##                                                                     #STR1077##                                                           R.sup.4 : H M.p. 234-235° C. Crystalline form: Yellow powder             Solvent for recrystallization: Dichloromethane-diethyl ether                   Form: Methanesulfonate                                                        __________________________________________________________________________

                                      TABLE 178                                    __________________________________________________________________________     Example 430                                                                              #STR1078##                                                                     #STR1079##                                                           R.sup.4 : H M.p. 195-200° C. (decomp.) Crystalline form: Pale           yellow powder                                                                    Solvent for recrystallization: Acetone-water-diethyl ether                     NMR (11) Form: Methanesulfonate                                              Example 431                                                                              #STR1080##                                                                     #STR1081##                                                           R.sup.4 : H M.p. 183-220° C. (decomp.) Crystalline form: White          powder                                                                           Solvent for recrystallization: Acetone-ethanol-diethyl ether                   NMR (12) Form: 2HCl                                                          Example 432                                                                              #STR1082##                                                                     #STR1083##                                                           R.sup.4 : H M.p. 159-161° C. Crystalline form: Yellow powder             Solvent for recrystallization: Ethanol-acetone-diethyl ether                   Form: 2HCl                                                                    __________________________________________________________________________

                                      TABLE 179                                    __________________________________________________________________________     Example 433                                                                              #STR1084##                                                                     #STR1085##                                                           R.sup.4 : H M.p. 177-180° C. Crystalline form: Yellow amorphous          Solvent for recrystallization: Ethanol-water-diethyl ether Form: 2HCl         Example 434                                                                              #STR1086##                                                                     #STR1087##                                                           R.sup.4 : H M.p. 178-181° C. Crystalline form: Yellow powder             Solvent for recrystallization: Ethanol-water Form: 2HCl                       Example 435                                                                              #STR1088##                                                                     #STR1089##                                                           R.sup.4 : H M.p. 199-202° C. Crystalline form: Pale orange powder        Solvent for recrystallization: Ethanol-water Form: Methanesulfonate           __________________________________________________________________________

                                      TABLE 180                                    __________________________________________________________________________     Example 436                                                                              #STR1090##                                                                     #STR1091##                                                           R.sup.4 : H NMR (13) Crystalline form: Yellow amorphous Form: 2HCl             Example 437                                                                              #STR1092##                                                                     #STR1093##                                                           R.sup.4 : H M.p. 151-154° C. Crystalline form: Yellow powder             Solvent for recrystallizaiton: Ethanol-diethyl ether Form: Methanesulfona     te                                                                             Example 438                                                                              #STR1094##                                                                     #STR1095##                                                           R.sup.4 : H M.p. 114-116° C. Crystalline form: Yellow powder             Solvent for recrystallization: Acetone-water Form: Methanesulfonate           __________________________________________________________________________

                                      TABLE 181                                    __________________________________________________________________________     Example 439                                                                              #STR1096##                                                                     #STR1097##                                                           R.sup.4 : H M.p. 205-208° C. Crystalline form: Yellow powder             Solvent for recrystallization: Acetone-water Form: 2HCl                       Example 440                                                                              #STR1098##                                                                     #STR1099##                                                           R.sup.4 : H M.p. 185-190° C. (decomp.) Crystalline form: Pale           yellow powder                                                                    Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether          NMR (14) Form: Methanesulfonate                                               Example 441                                                                              #STR1100##                                                                     #STR1101##                                                           R.sup.4 : H M.p. 160-180° C. (decomp.) Crystalline form: Pale           yellow powder                                                                    Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether          NMR (15) Form: 2HCl                                                           __________________________________________________________________________

                                      TABLE 182                                    __________________________________________________________________________     Example 442                                                                              #STR1102##                                                                     #STR1103##                                                           R.sup.4 : H M.p. 170-190° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether           NMR (16) Form: 2HCl                                                           Example 443                                                                              #STR1104##                                                                     #STR1105##                                                           R.sup.4 : H M.p. 178-183° C. (decomp.) Crystalline form: Pale           yellow powder                                                                    Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether          NMR (17) Form: 2HCl                                                           Example 445                                                                              #STR1106##                                                                     #STR1107##                                                           R.sup.4 : H M.p. 138-150° C. (decomp.) Crystalline form: Pale           brown powder                                                                     Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether          NMR (18) Form: Methanesulfonate                                               __________________________________________________________________________

                                      TABLE 183                                    __________________________________________________________________________     Example 446                                                                              #STR1108##                                                                     #STR1109##                                                           R.sup.4 : H M.p. 120-160° C. (decomp.) Crystalline form: Pale           brown powder                                                                     Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether-ace     tone                                                                            NMR (19) Form: Methanesulfonate                                               Example 447                                                                              #STR1110##                                                                     #STR1111##                                                           R.sup.4 : H M.p. 169-171° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-water Form: 2HCl                       Example 448                                                                              #STR1112##                                                                     #STR1113##                                                           R.sup.4 : H M.p. 178-180° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-water-diethyl ether Form:              __________________________________________________________________________     2HCl                                                                      

                                      TABLE 184                                    __________________________________________________________________________     Example 449                                                                              #STR1114##                                                                     #STR1115##                                                           R.sup.4 : H M.p. 162-164° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-water-diethyl ether                     Form: 2HCl                                                                    Example 450                                                                              #STR1116##                                                                     #STR1117##                                                           R.sup.4 : H M.p. 172-175° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-water Form: 2HCl                       Example 451                                                                              #STR1118##                                                                     #STR1119##                                                           R.sup.4 : H M.p. 167-170° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-water Form: 2HCl                       __________________________________________________________________________

                                      TABLE 185                                    __________________________________________________________________________     Example 452                                                                              #STR1120##                                                                     #STR1121##                                                           R.sup.4 : H M.p. 208-209° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-water                                   Form: Methanesulfonate                                                        Example 453                                                                              #STR1122##                                                                     #STR1123##                                                           R.sup.4 : H M.p. 246-249° C. Crystalline form: Yellow powder             Solvent for recrystallization: Ethanol-water Form: 2HCl                       Example 454                                                                              #STR1124##                                                                     #STR1125##                                                           R.sup.4 : H M.p. 188-190° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-water Form: 2HCl                       __________________________________________________________________________

                                      TABLE 186                                    __________________________________________________________________________     Example 455                                                                              #STR1126##                                                                     #STR1127##                                                           R.sup.4 : H M.p. 167-169° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-water Form: 2HCl                       Example 456                                                                              #STR1128##                                                                     #STR1129##                                                           R.sup.4 : H M.p. 170-173° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-water Form: 2HCl                       Example 457                                                                              #STR1130##                                                                     #STR1131##                                                           R.sup.4 : H M.p. 225-228° C. Crystalline form: Pale yellow powder        Solvent for recrystallization: Ethanol-dichloromethane Form: 2HCl             __________________________________________________________________________

                                      TABLE 187                                    __________________________________________________________________________     Example 458                                                                              #STR1132##                                                                     #STR1133##                                                           R.sup.4 : H M.p. 162.0-163.5° C. Crystalline form: Yellow powder         Solvent for recrystallization: Ethanol-water Form: Methanesulfonate           Example 459                                                                              #STR1134##                                                                     #STR1135##                                                           R.sup.4 : H M.p. 209.5-212.5° C. Crystalline form: White powder          Solvent for recrystallization: Ethanol-water Form: 3HCl                       Example 460                                                                              #STR1136##                                                                     #STR1137##                                                           R.sup.4 : H M.p. 155-185° C. (decomp.) Crystalline form: Pale           yellow powder                                                                    Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether          NMR (20) Form: Methanesulfonate                                               __________________________________________________________________________

                                      TABLE 188                                    __________________________________________________________________________     Example 461                                                                              #STR1138##                                                                     #STR1139##                                                           R.sup.4 : H M.p. 180-215° C. (decomp.) Crystalline form: Pale           yellow powder                                                                    Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether          NMR (21) Form: 2HCl                                                           Example 462                                                                              #STR1140##                                                                     #STR1141##                                                           R.sup.4 : H M.p. 220-225° C. (decomp.) Crystalline form: Pale           yellow powder                                                                    Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether          NMR (22) Form: 2HCl                                                           Example 463                                                                              #STR1142##                                                                     #STR1143##                                                           R.sup.4 : H M.p. 180-215° C. (decomp.) Crystalline form: Pale           yellow powder                                                                    Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether          NMR (23) Form: 2HCl                                                           __________________________________________________________________________

                                      TABLE 189                                    __________________________________________________________________________     Example 464                                                                              #STR1144##                                                                     #STR1145##                                                           R.sup.4 : H M.p. 185.5-192° C. Crystalline form: Yellow powder           Solvent for recrystallization: Ethanol-water                                   NMR (24) Form: 2HCl                                                           Example 465                                                                              #STR1146##                                                                     #STR1147##                                                           R.sup.4 : H M.p. 159.5-161.2° C. Crystalline form: Pale yellow          powder                                                                           Solvent for recrystallization: Ethanol-diethyl ether-water Form: 2HCl        Example 466                                                                              #STR1148##                                                                     #STR1149##                                                           R.sup.4 : H M.p. 150-158° C. (decomp.) Crystalline form: Pale           yellow powder                                                                    Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether          NMR (25) Form: Methanesulfonate                                               __________________________________________________________________________

                                      TABLE 190                                    __________________________________________________________________________     Example 467                                                                             #STR1150##                                                                     #STR1151##                                                               -                                                                           R.sup.4: H                                                                          M.p. 193-204° C. (decomp.)                                         Crystalline form: Pale yellow powder                                             Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether         NMR (26) Form: 2HCl                                                            Example 468                                                                             #STR1152##                                                                     #STR1153##                                                               -                                                                           R.sup.4: H                                                                          M.p. 205-213° C. (decomp.)                                         Crystalline form: Pale yellow powder                                             Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether         NMR (27)                                                                            Form: 2HCl                                                                Example 469                                                                             #STR1154##                                                                     #STR1155##                                                               -                                                                           R.sup.4: H                                                                        M.p. 205-213° C. (decomp.) Crystalline form: Pale yellow powder      Solvent for recrystallization: Ethanol-dichloromethane-diethyl ether           NMR (28) Form: 2HCl                                                            __________________________________________________________________________

                                      TABLE 191                                    __________________________________________________________________________     Example 470                                                                             #STR1156##                                                                     #STR1157##                                                               -                                                                           R.sup.4: H                                                                          M.p. 131-160° C. (decomp.)                                         Crystalline form: Pale yellow powder                                             Solvent for recrystallization: Dichloromethane-ethanol-diethyl ether         NMR (29) Form: Methanesulfonate                                                Example 471                                                                             #STR1158##                                                                     #STR1159##                                                               -                                                                           R.sup.4: H                                                                        M.p. 180-210° C. (decomp.)                                                              Crystalline form: Pale brown powder                         Solvent for recrystallization: Dichloromethane-ethanol-diethyl ether           NMR (30) Form: 2HCl                                                            Example 472                                                                             #STR1160##                                                                     #STR1161##                                                               -                                                                           R.sup.4: H                                                                        M.p. 231-235° C. (decomp.)                                                              Crystalline form: Pale yellow powder                        Solvent for recrystallization: Dichloromethane-ethanol-diethyl ether            Form: 2HCl                                                                    __________________________________________________________________________

                                      TABLE 192                                    __________________________________________________________________________     Example 473                                                                             #STR1162##                                                                     #STR1163##                                                               -                                                                           R.sup.4: H                                                                          M.p. 216-221° C. (decomp.)                                         Crystalline form: Pale yellow powder                                             Solvent for recrystallization: Dichloromethane-ethanol-diethyl ether         NMR (31) Form: 2HCl                                                            Example 474                                                                             #STR1164##                                                                     #STR1165##                                                               -                                                                           R.sup.4: H                                                                        M.p. 175-205° C. (decomp.)                                                              Crystalline form: Pale yellow powder                        Solvent for recrystallization: Dichloromethane-ethanol-diethyl ether           NMR (32) Form: Methanesulfonate                                                Example 475                                                                             #STR1166##                                                                     #STR1167##                                                               -                                                                           R.sup.4: H                                                                        M.p. 185-230° C. (decomp.)                                                              Crystalline form: Pale yellow powder                        Solvent for recrystallization: Dichloromethane-ethanol-diethyl ether           NMR (33) Form: 2HCl                                                            __________________________________________________________________________

                                      TABLE 193                                    __________________________________________________________________________     Example 476                                                                             #STR1168##                                                                     #STR1169##                                                               -                                                                           R.sup.4: H                                                                        M.p. 160-170° C.                                                     Crystalline form: Pale yellow powder                                             Solvent for recrystallization: Ethanol-water                                 NMR (34) Form: Dimethanesulfonate                                              Example 477                                                                             #STR1170##                                                                     #STR1171##                                                               -                                                                           R.sup.4: H                                                                        M.p. 172-178° C.                                                                      Crystalline form: Pale yellow powder                          Solvent for recrystallization: Ethanol-water                                                      NMR (35)                                                                             Form: 3HCl                                            Example 478                                                                             #STR1172##                                                                     #STR1173##                                                               -                                                                           R.sup.4: H                                                                        M.p. 185.2-186.0° C.                                                                  Crystalline form: White powder                                Solvent for recrystallization: Ethanol                                                                  Form: Free                                            __________________________________________________________________________

Using the suitable starting compounds, the compounds as listed in Table 194 are obtained in the same manner as in Example 8.

                                      TABLE 194                                    __________________________________________________________________________      ##STR1174##                                                                   __________________________________________________________________________     Example 479                                                                             #STR1175##                                                                     #STR1176##                                                               -                                                                           R.sup.4: H                                                                          M.p. 171.5-173.0° C.                                               Crystalline form: Pale yellow powder                                             Solvent for recrystallization: Ethanol-diethyl ether-dichloromethane          Form: 2HCl                                                                    Example 480                                                                             #STR1177##                                                                     #STR1178##                                                               -                                                                           R.sup.4: H                                                                        M.p. 111.5-114.5° C.                                                                  Crystalline form: Pale yellow powder                          Solvent for recrystallization: Ethanol-water-isopropyl alcohol                                            Form: 2HCl                                          __________________________________________________________________________

Using the suitable starting compounds, the compound as listed in Table 195 are obtained in the same manner as in Example 3 or 4.

                                      TABLE 195                                    __________________________________________________________________________      ##STR1179##                                                                   __________________________________________________________________________     Example 481                                                                             #STR1180##                                                                     #STR1181##                                                               -                                                                           R.sup.4: H                                                                            T: --CH.sub.2 --                                                                     u:1                                                               M.p. 147-150° C.                                                                 Crystalline form: Pale yellow powder                                  Solvent for recrystallization: Ethanol-water-diethyl ether-isopropyl           alcohol                                                                          Form: 2HCl                                                                   __________________________________________________________________________

¹ H-NMR spectrum (NMR (1) to NMR (49)) as described in Tables 150-195 are as follows:

NMR (1) (DMSO-d₆) δppm: 2.65-2.8 (4H, m), 3.06 (9H, s), 3.87 (3H, s), 4.15-4.65 (4H, m), 5.07 (2H, s), 6.70 (1H, dd, J=2 Hz, J=8.5 Hz), 6.81 (1H, d, J=2 Hz), 7.29 (1H, d, J=15 Hz), 7.48 (1H, br), 7.62 (1H, d, J=15 Hz), 7.65 (1H, d, J=8.5 Hz), 7.77 (1H, d, J=9 Hz), 7.93 (1H, br), 11.0 (1H, br), 12.7 (1H, br); NMR (2) (DMSO-d₆) δppm: 1.65 (2H, br), 2.05-2.40 (4H, m), 2.55-2.9 (4H, m), 3.13 (6H, s), 3.25-4.8 (15H, m), 5.10 (2H, s), 6.70 (1H, dd, J=2 Hz, J=9 Hz), 6.81 (1H, d, J=2 Hz), 7.26 (1H, d, J=15 Hz), 7.55 (1H, d, J=15 Hz), 7.64 (1H, d, J=8.5 Hz), 7.7-7.8 (1H, m), 7.88 (1H, d, J=9 Hz), 8.31 (1H, br), 11.2-12.2 (2H, m); NMR (3) (DMSO-d₆) δppm: 1.61 (3H, d, J=6.5 Hz), 1.6 (2H, br), 2.12 (4H, br), 2.5-2.85 (4H, m), 2.95-4.05 (13H, m), 4.1-4.3 (1H, m), 4.4-4.7 (1H, m) 5.35 (1H, q, J=6.5 Hz), 6.63 (1H, dd, J=2 Hz, 9 Hz), 6.77 (1H, d, J=2 Hz), 7.15-7.7 (4H, m), 7.69 (1H, d, J=9 Hz), 7.76 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7.5 Hz), 11.1-13.1 (3H, m); NMR (4) (DMSO-d₆) δppm: 1.61 (3H, d, J=6.5 Hz), 2.73 (3H, d, J=4 Hz), 2.8-4.1 (6H, m), 3.85 (3H, s), 4.1-4.35 (1H, m), 4.35-4.6 (1H, m), 5.38 (1H, q, J=6.5 Hz), 6.63 (1H, dd, J=2 Hz, 9 Hz), 6.78 (1H, d, J=2 Hz), 7.26 (1H, d, J=15 Hz), 7.25-7.5 (2H, m), 7.59 (1H, d, J=15 Hz), 7.63(1H, d, J=9 Hz), 7.76 (1H, d, J=7.5 Hz), 7.97 (1H, d, J=7 Hz), 11.40 (1H, br), 12.9 (1H, br); NMR (5) (DMSO-d₆) δppm: 1.61 (3H, d, J=6.5 Hz), 2.35-4.4 (23H, m), 5.37 (1H, q, J=6.5 Hz), 6.63 (1H, dd, J=2 Hz, J=8.5 Hz), 6.78 (1H, d, J=2 Hz), 7.1-7.7 (5H, m), 7.76 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7 Hz), 11.85 (2H, br) 12.90 (1H, br); NMR (6) (DMSO-d₆) δppm: 2.42 (6H, s), 2.82 (3H, d, J=4 Hz), 2.9-3.25 (3H, m), 3.3-3.6 (3H, m), 4.15-4.6 (6H, m), 5.03 (2H, s), 6.68 (1H, d, J=9 Hz), 7.23 (1H, d, J=9 Hz), 7.31 (1H, d, J=15 Hz), 7.15-7.5 (2H, m), 7.61 (1H, d, J=15 Hz), 7.76 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7 Hz), 9.85 (1H, br); NMR (7) DMSO-d₆) δppm: 1.64 (2H, br), 2.17 (4H, br), 2.55-2.7 (4H, m), 2.95-4.0 (10H, m), 4.05-4.7 (6H, m), 5.03 (2H, s), 6.68 (1H, d, J=9 Hz), 7.22 (1H, d, J=9 Hz), 7.25-7.6 (4H, m), 7.76 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7.5 Hz), 11.1-12.2 (2H, m), 12.65 (1H, br); NMR (8) (DMSO-d₆) δppm: 2.55-2.7 (1H, m), 2.79 (3H, s), 2.85-4.5 (20H, m), 5.04 (2H, s), 6.68 (1H, d, J=8.5 Hz), 7.15-7.7 (5H, m), 7.76 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7 Hz), 11.4-13.1 (2H, m); NMR (9) (DMSO-d₆) δppm: 1.35 (3H, d, J=5.5 Hz), 1.64 (2H, br), 2.14 (2H, br), 2.55-2.95 (4H, m), 2.95-4.0 (9H, m), 6.0 (1H, d, J=9 Hz), 7.22 (1H, d, J=9 Hz), 7.29 (1H, d, J=15.5 Hz), 4.05-4.7 (6H, m), 5.03 (2H, s), 7.4-7.5 (1H, m), 7.53 (1H, d, J=15.5 Hz), 7.76 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7 Hz), 11.5-13.0 (2H, m); NMR (10) (DMSO-d₆) δppm; 2.16 (3H, s), 2.37 (3H, s), 2.77 (3H, d, J=4.2 Hz), 2.83-3.19 (3H, m), 3.29-3.58 (3H, m), 3.88 (3H, s), 4.12-4.57 (2H, m), 4.65 (2H,s), 6.95 (1H, d, J=8.8 Hz), 7.19-7.37 (2H, m), 7.37-7.50 (1H, m), 7.50-7.66 (2H, m), 7.75 (1H, d, J=7.9 Hz), 7.99 (1H, d, J=7.9 Hz), 9.82 (1H, brs), 11.95-12.71 (1H, m); NMR (11) (DMSO-d₆) δppm; 2.17 (2H, br), 2.34 (3H, s), 2.82 (3H, s), 3.05 (4H, br), 3.4 (2H, br), 4.05-4.4 (5H, m), 4.49 (1H, br), 5.05 (2H, s), 6.83 (1H, d, J=9 Hz), 7.28 (1H, d, J=15 Hz), 7.29 (1H, d, J=9 Hz), 7.25-7.35 (1H, m), 7.35-7.5 (1H, m), 7.52 (1H, d, J=15 Hz), 7.76 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7 Hz), 9.81 (1H, br), 12.6 (1H, br); NMR (12) DMSO-d₆) δppm; 1.61 (2H, br), 2.15 (4H, br), 2.55-2.9 (4H, m), 3.0-4.3 (11H, m), 4.4-4.7 (1H, m), 5.09 (2H, s), 7.12 (1H, dd, J=2.5 Hz, J=8.5 Hz), 7.25-7.41 (4H, m), 7.4-7.5 (1H, m), 7.69 (1H, d, J=8.5 Hz), 7.77 (1H, d, J=7.5 Hz), 7.99 (1H, d, J=7 Hz), 11.0-12.2 (2H, m); NMR (13) (DMSO-d₆) δppm; 0.91 (3H, t, J=7.2 Hz), 1.20-1.86 (6H, m), 1.93-2.39 (4H, m), 2.58-2.89 (4H, m), 2.76 (3H, s), 2.95-3.98 (9H, m), 3.64 (3H, s), 4.07-4.31 (1H, m), 4.41-4.69 (1H, m), 5.09 (2H, s), 6.83 (1H, d, J=8.9 Hz), 7.20-7.64 (5H, m), 7.76 (1H, d, J=7.9 Hz), 7.97 (1H, d, J=7.9 Hz), 11.11-12.29 (2H, m), 12.72 (1H, brs); NMR (14) (DMSO-d₆) δppm; 2.0-2.2 (2H, m), 2.34 (3H,s), 2.68 (2H, t, J=7 Hz), 2.81 (3H, d, J=3 Hz), 2.9-3.2 (2H, m), 3.3-3.65 (4H, m), 3.79 (3H, s), 4.15 (2H, t, J=6 Hz), 4.2-4.4 (1H, m), 4.4-4.6 (1H, m), 6.55-6.7 (2H, m), 7.2-7.35 (1H, m), 7.27 (1H, d, J=15 Hz), 7.35-7.5 (1H, m), 7.63 (1H, d, J=9.5 Hz), 7.63 (1H, d, J=15 Hz), 7.72 (1H, d, J=7.5 Hz), 7.9-8.0 (1H, m), 9.79 (1H, br), 12.38 (1H, br); NMR (15) (DMSO-d₆) δppm; 1.64 (2H, br), 2.0-2.4(6H, m), 2.55-2.9 (6H,m), 2.95-4.0 (3H, m), 4.0-4.35 (3H, m), 4.4-4.7 (1H, m), 6.55-6.75 (2H, m), 7.0 (1H, br), 7.2-7.35 (2H, m), 7.35-7.45 (1H, m), 7.5-7.65 (2H, m), 7.65-7.75 (1H, m), 7.9-8.0 (1H, m), 11.2-12.6 (2H, m); NMR (16) DMSO-d₆) δppm; 2.0-2.2 (2H, m), 2.69 (2H, t, J=7 Hz), 2.80 (3H, s), 2.9-4.4 (22H, m), 6.4-6.75 (2H, m), 7.15-7.5 (3H, m), 7.5-7.8 (3H, m), 7.96 (1H, d, J=7 Hz), 11.95 (1H, br), 12.41 (1H, br); NMR (17) (DMSO-d₆) δppm; 1.45-1.9 (2H, m), 2.0-2.35 (4H, m), 2.55-2.95 (6H, m), 2.95-3.25 (1H, m), 3.3-3.95 (12H, m), 4.0-4.35 (3H, m), 4.4-4.65 (1H, m), 6.4-6.75 (2H, m), 7.25 (1H, d, J=15 Hz), 7.2-7.5 (2H, m), 7.55 (1H, d, J=15 Hz), 7.61 (1H, d, J=9.5 Hz), 7.71 (1H, d, J=7.5 Hz), 7.96 (1H, d, J=7 Hz), 11.9-12.8 (2H,m); NMR (18) (DMSO-d₆) δppm; 1.16 (3H, t, J=7.5 Hz), 1.9-2.2 (2H, m), 2.48 (3H, s), 2.62 (2H, q, J=7.5 Hz), 2.82 (3H, d, J=4.5 Hz), 3.0-3.8 (5H, m), 3.84 (3H, s), 3.9-4.3 (3H, m), 5.16 (2H, s), 6.71 (1H, s), 7.22 (1H, d, J=15 Hz), 7.25-7.35 (1H, m), 7.4-7.5 (1H, m), 7.51 (1H, s), 7.66 (1H, dd, J=5.5 Hz, J=15 Hz), 7.77 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7 Hz), 9.55 (1H, br), 11.7 (1H,br); NMR (19) (DMSO-d₆) δppm; 1.15 (3H, t, J=7.5 Hz), 1.35-1.7 (2H, m), 1.9-2.1 (2H, m), 2.36 (3H, s), 2.5-2.7 (3H, m), 2.73 (3H, s), 2.75 (3H, s), 3.0-3.2 (1H, m), 3.3-3.55 (1H, m), 3.84 (3H, s), 4.05-4.25 (1H, m), 4.45-4.65 (1H, m), 5.16 (2H, s), 6.71 (1H, s), 7.26 (1H, d, J=15 Hz), 7.25-7.35 (1H, m), 7.4-7.5 (1H, m), 7.50 (1H, s), 7.58 (1H, d, J=15 Hz), 7.77 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7 Hz), 9.58 (1H, br); NMR (20) (DMSO-d₆) δppm; 0.90 (3H, t, J=7.5 Hz), 1.57 (2H, tq, J=7.5 Hz, J=8 Hz), 2.35 (3H, s), 2.57 (2H, t, J=8 Hz), 2.81 (3H, d, J=3.5 Hz), 2.9-3.25 (3H, m), 3.3-3.7 (3H, m), 3.83 (3H, s), 4.15-4.4 (1H, m), 4.4-4.65 (1H, m), 5.16 (2H, s), 6.70 (1H, s), 7.28 (1H, d, J=15 Hz), 7.25-7.4 (1H, m), 7.4-7.5 (1H, m), 7.49 (1H, s), 7.66 (1H, d, J=15 Hz), 7.77 (1H, d, J=8 Hz), 7.98 (1H, d, J=7.5 Hz), 9.85 (1H, br) 12.6 (1H, br); NMR (21) (DMSO-d₆) δppm; 0.89 (3H, t, 7.5 Hz), 1.4-1.9 (4H, m), 2.0-2.4 (4H, m), 2.5-2.85 (6H, m), 3.0-4.05 (10H, m), 3.84 (3H, s), 4.05-4.3 (1H, m), 4.45-4.7 (1H, m), 5.17 (2H, s), 6.71 (1H, s), 7.15-7.35 (2H, m), 7.35-7.5 (1H, m), 7.48 (1H, s), 7.58 (1H, d, J=15 Hz), 7.77 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7 Hz), 11.1-13.2 (2H, m); NMR (22) (DMSO-d₆) δppm; 0.90 (3H, t, J=7.5 Hz), 1.4-1.8 (4H, m), 1.95-2.25 (2H, m), 2.57 (2H, t, J=8 Hz), 2.6-2.9 (1H, m), 2.81 (3H, s), 2.95-4.0 (10H, m), 3.84 (3H, s), 4.05-4.3 (1H, m), 4.4-4.65 (1H, m), 5.16 (2H, s), 6.70 (1H, s), 7.26 (1H, d, J=15 Hz), 7.25-7.35 (1H, m), 7.35-7.5 (1H, m), 7.48 (1H, s), 7.58 (1H, d, J=15 Hz), 7.77 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7 Hz), 11.4-13.0 (3H, m); NMR (23) (DMSO-d₆) δppm; 0.90 (3H, t, J=7.5 Hz), 1.57 (2H, tq, J=7.5 Hz, J=8 Hz), 2.57 (2H, t, J=8 Hz), 2.65-4.4 (17H, m), 2.79 (3H, s), 3.84 (3H, s), 5.18 (2H, s), 6.71 (1H, s), 7.15-7.5 (3H, m), 7.48 (1H, s), 7.5-7.8 (2H, m), 7.98 (1H, d, J=7 Hz), 11.0-13.0 (3H, m); NMR (24) (DMSO-d₆) δppm; 1.11 (3H, t, J=7.4 Hz), 2.53-4.17 (16H, m), 2.59 (2H, q, J=7.4 Hz), 2.79 (3H, s), 3.84 (3H, s), 4.17-4.40 (1H, m), 5.20 (2H, s), 6.73 (1H, s), 7.18-7.38 (2H, m), 7.38-7.54 (2H, m), 7.54-7.74 (1H, m), 7.74-7.81 (1H, m), 7.92-8.05 (1H, m), 11.32-13.11 (3H, m); NMR (25) (DMSO-d₆) δppm; 2.35 (3H, s), 2.80 (3H, d, J=3.5 Hz), 2.85-3.6 (6H, m), 3.85 (3H, s), 4.04 (2H, br), 4.2-4.6 (2H, m), 5.0-5.25 (4H, m), 5.81-6.1 (1H, m), 6.74 (1H, s), 7.28 (1H, d, J=15 Hz), 7.25-7.55 (2H, m), 7.48(1H, s), 7.65 (1H, d, J=15 Hz), 7.77 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7 Hz), 9.99 (1H, br), 12.6 (1H, br); NMR (26) (DMSO-d₆) δppm; 1.65 (2H, br), 2.0-2.4 (4H, m), 2.55-2.95 (4H, m), 3.0-3.25 (1H, m), 3.25-4.05 (14H, m), 4.05-4.3 (1H, m), 4.45-4.7 (1H, m), 4.95-5.3 (4H, m), 5.85-6.1 (1H, m), 6.75 (1H, s), 7.15-7.7 (5H, m), 7.77 (1H, d, J=8 Hz), 7.98 (1H, d, J=7.5 Hz), 11.1-13.0 (3H, m); NMR (27) (DMSO-d₆) δppm; 1.4-1.85 (2H, m), 1.95-2.3 (2H, m), 2.55-2.95 (4H, m), 2.95-3.2 (1H, m), 3.2-3.95 (11H, m), 5.86 (3H, s), 4.1-4.3 (1H, m), 4.45-4.7 (1H, m), 4.95-5.25 (4H, m), 5.86-6.1 (1H, m), 6.74 (1H, s), 7.26 (1H, d, J=15 Hz), 7.25-7.55 (3H, m), 7.56 (1H, d, J=15 Hz), 7.77 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7 Hz), 11.3-13.2 (3H, m); NMR (28) (DMSO-d₆) δppm; 2.55-4.45 (25H, m), 4.9-5.3 (4H, m), 5.85-6.1 (1H, m), 6.75 (1H, s), 7.15-7.85 (6H, m), 7.98 (1H, d, J=7 Hz), 11.0-13.3 (3H, m); NMR (29) (DMSO-d₆) δppm; 1.32 (3H, t, J=7 Hz), 2.33 (3H, s), 2.80 (3 H,s), 2.9-3.2 (3H, m), 3.3-3.5 (3H, m), 3.81 (3H, s), 4.03 (2H, q, J=7 Hz), 4.2-4.65 (2H, m), 5.15 (2H, s), 6.83 (1H, s), 7.2-7.4 (3H, m), 7.44 (1H, t, J=8 Hz), 7.69 (1H, d, J=15 Hz), 7.77 (1H, d, J=8 Hz), 7.98 (1H, d, J=8 Hz), 9.83 (1H, br), 12.60 (1H, br); NMR (30) (DMSO-d₆) δppm; 1.32 (3H, t, J=7 Hz), 1.4-1.9 (2H, m), 2.05-2.4 (4H, m), 2.6-3.9 (4H, m), 3.05-3.95 (13H, m), 4.03 (2H, q, J=7 Hz), 4.1-4.3 (1H, m), 4.5-4.7 (1H, m), 5.17 (2H, s), 6.83 (1H, s), 7.2-7.4 (3H, m), 7.44 (1H, t, J=8 Hz), 7.60 (1H, d, J=15.5 Hz), 7.76 (1H, d, J=8 Hz), 7.98 (1H, d, J=8 Hz), 11.25-12.2 (2H, m); NMR (31) (DMSO-d₆) δppm; 1.32 (3H, t, J=7 Hz), 2.55-4.5 (19H, m), 2.80 (3H, s), 3.82 (3H, s), 5.17 (2H, s), 6.84 (1H, s), 7.2-7.4 (3H, m), 7.44 (1H, t, J=8 Hz), 7.64 (1H, d, J=15.5 Hz), 7.76 (1H, d, J=8 Hz), 7.98 (1H, d, J=8 Hz), 11.5-12.5 (2H, m); NMR (32) DMSO-d₆) δppm; 2.32 (3H, s), 2.81 (3H, s), 3.4-3.7 (4H, m), 3.25-3.6 (2H, m), 3.86 (3H, s), 4.15-4.65 (2H, m), 5.26 (2H, s), 6.89 (1H, s), 7.32 (1H, d, J=15 Hz), 7.32 (1H, t, J=7.5 Hz), 7.45 (1H, t, J=8 Hz), 7.61 (1H, d, J=15 Hz), 7.77 (1H, d, J=8 Hz), 7.83 (1H,s), 7.98 (1H, d, J=7.5 Hz), 9.78 (1H, br), 12.65 (1H, br); NMR (33) DMSO-d₆) δppm; 1.4-1.85 (2H, m), 2.1-2.4 (4H, m), 2.6-3.9 (4H, m), 3.05-4.5 (14H, m), 4.5-4.65 (1H, m), 5.27 (2H, s), 6.89 (1H, s), 7.2-7.4 (2H, m), 7.4-7.6 (2H, m), 7.77 (1H, d, J=8 Hz), 7.81 (1H, s), 7.98 (1H, d, J=8 Hz), 11.1-12.1 (2H, m); NMR (34) (DMSO-d₆) δppm; 2.35(s, 6H), 2.82 (s, 3H), 2.92-3.27 (m, 9H), 3.30-3.59 (m, 3H), 4.18 (br, 1H), 4.19-4.34 (m, 1H), 4.47-4.65 (m, 1H), 5.24 (s, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.44 (d, J=7.3 Hz, 1H), 7.46 (d, J=15.1 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.84 (d, J=15.1 Hz, 1H), 7.96-8.15 (m, 3H), 9.82 (br, 1H), 12.66 (br, 1H); NMR (35) (DMSO-d₆) δppm; 1.42-1.88 (m, 2H), 1.93-2.39(m, 4H), 2.59-2.85 (m, 4H), 3.13 (s, 6H), 3.26-3.96 (m, 10H), 4.05-4.28 (m, 1H), 4.51-4.68 (m, 1H), 5.26 (s, 2H), 7.29-7.35 (m, 2H), 7.42-7.48 (m, 2H), 7.74-7.80 (m, 2H, 7.96-8.04 (m, 2H), 8.19 (br, 1H), 11.35-12.13 (m, 2H); NMR (36) (DMSO-d₆) δppm; 4.61-4.78 (2H, m), 5.05 (2H, s), 5.18-5.50 (2H, m), 5.91-6.17 (1H, m), 6.46 (1H, d, J=15.5 Hz), 6.62-6.78 (1H, m), 6.78-6.88 (1H, m), 7.28-7.39 (1H, m), 7.39-7.52 (1H, m), 7.54-7.81 (2H, m), 7.71 (1H, d, J=15.5 Hz), 7.92-8.05 (1H, m), 12.72 (2H, brs); NMR (37) DMSO-d₆) δppm; 4.97 (2H, s), 6.40-6.58 (2H, m), 6.91 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.00-7.22 (3H, m), 7.22-7.51 (4H, m), 7.61-7.89 (3H, m), 7.89-8.04 (1H, m), 12.75 (2H, brs); NMR (38) DMSO-d₆) δppm; 1.12 (3H, t, J=7.4 Hz), 2.60 (2H, q, J=7.4 Hz), 3.85 (3H, s), 5.15 (2H, s), 6.46 (1H, d, J=15.5 Hz), 6.71 (1H, s), 7.26-7.39 (1H, m), 7.39-7.50 (1H, m), 7.51 (1H, s), 7.68 (1H, d, J=15.5 Hz), 7.72-7.81 (1H, m) 7.91-8.03 (1H, m), 12.75 (2H, brs); NMR (39) DMSO-d₆) δppm; 2.19 (3H, s), 3.64 (3H, s), 5.07 (2H, s), 6.54 (1H, d, J=15.6 Hz), 6.85 (1H, d, J=8.7 Hz), 7.25-7.40 (1H, m), 7.40-7.51 (1H, m), 7.54 (1H, d, J=8.8 Hz), 7.68 (1H, d, J=15.6 Hz), 7.76 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=7.5 Hz), 12.41-13.16 (2H, m); NMR (40) (DMSO-d₆) δppm; 2.16 (3H, s), 3.88 (3H, s), 4.64 (2H, s), 6.52 (1H, d, J=15.6 Hz), 6.95 (1H, d, J=8.8 Hz), 7.21-7.38 (1H, m), 7.38-7.51 (1H, m), 7.55-7.80 (3H, m), 7.98 (1H, d, J=7.1 Hz); NMR (41) (DMSO-d₆) δppm; 0.91 (3H, t, J=7.3 Hz), 1.20-1.65 (4H, m), 2.54-2.78 (2H, m), 3.63 (3H, s), 5.07 (2H, s), 6.58 (1H, d, J=15.6 Hz), 6.84 (1H, d, J=8.7 Hz), 7.21-7.39 (1H, m), 7.39-7.51 (1H, m), 7.55 (1H, d, J=8.7 Hz), 7.67 (1, d, J=15.6 Hz), 7.76 (1H, d, J=7.8 Hz), 7.97 (1H, d, J=7.8 Hz), 12.05-13.51 (2H, m); NMR (42) (DMSO-d₆) δppm; 2.41 (3H, s), 5.10 (2H, s), 6.56 (1H, d, J=15.5 Hz), 6.90 (1H, dd, J=8.8 Hz, J=2.2 Hz), 6.98 (1H, d, J=2.2 Hz), 7.32 (1H, t, J=7.2 Hz), 7.45 (1H, t, J=7.2 Hz), 7.65-7.85 (2H, m), 7.99 (1H, d, J=7.7 Hz), 8.05 (1H, d, J=8.8 Hz), 12.06-13.45 (2H, m); NMR (43) DMSO-d₆) δppm; 1.17 (3H, t, J=7.5 Hz), 2.70 (2H, q, J=7.5 Hz), 3.65 (3H, s), 5.09 (2H, s), 6.57 (1H, d, J=15.6 Hz), 6.85 (1H, d, J=8.9 Hz), 7.30 (1H, dt, J=1.2 Hz, J=7.1 Hz), 7.43 (1H, dt, J=1.2 Hz, J=7.1 Hz), 7.56 (1H, d, J=8.9 Hz), 7.67 (1H, d, J=15.6 Hz), 7.76 (1H, d, J=7.1 Hz), 7.97 (1H, d, J=7.1 Hz), 12.51-13.12 (2H, m); NMR (44) (DMSO-d₆) δppm; 3.79 (3H, s), 3.83 (3H, s), 5.12 (2H, s), 6.51 (1H, d, J=15.5 Hz), 6.84 (1H, s), 7.15-7.54 (3H, m with 1H s at 7.26), 7.61-7.86 (2H, m with 1H, d at 7.76 J=15.5 Hz), 7.99 (1H, d, J=7.1 Hz), 12.20-13.25 (2H, m); NMR (45) DMSO-d₆) δppm; 2.19 (3H, s), 3.85 (3H, s), 5.14 (2H, s), 6.49 (1H, d, J=15.5 Hz), 6.70 (1H, s), 7.20-7.56 (3H, m, with 1H s at 7.52), 7.60-7.82 (2H, m, with 1H d at 7.71 J=15.5 Hz), 7.98 (1H, d, J=7.0 Hz), 12.41-13.17(2H, m); NMR (46) DMSO-d₆) δppm; 1.19 (6H, d, J=6.9 Hz), 3.10-3.42 (1H, m), 3.86 (3H, s), 5.16 (2H, s), 6.50 (1H, d, J=15.5 Hz), 6.70 (1H, s), 7.21-7.60 (3H, m with 1H s at 7.55), 7.65-7.82 (2H, m with 1H d at 7.73 J=15.5 Hz), 7.89-8.08 (1H, m), 12.42-13.12 (2H, m); NMR (47) (DMSO-d₆) δppm; 0.68-0.92 (3H, m), 1.08-1.64 (8H, m), 2.38-2.68 (2H, m), 3.85 (3H, s), 5.14 (2H, s), 6.49 (1H, d, J=15.5 Hz), 6.71 (1H, s), 7.20-7.57 (3H, m), 7.62-7.85 (2H, m with 1H d at 7.72 J=15.5 Hz), 7.88-8.05 (1H, m), 12.45-13.12 (2H, m); NMR (48) (DMSO-d₆) δppm; 3.17 (s, 6H), 5.28 (s, 2H), 6.71 (d, J=15.5 Hz, 1H), 7.29-7.49 (m, 3H), 7.78 (d, J=8.0 Hz, 1H), 7.91-8.06 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 8.25 (s, 1H); NMR (49) (DMSO-d₆) δppm; 3.87 (s, 3H), 4.75 (d, J=5 Hz, 2H), 4.77 (s, 2H), 6.50 (d, J=15.5 Hz, 1H), 6.72 (dd, J=2.2 Hz J=8.6 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H), 7.33-7.57 (m, 2H), 7.66 (d, J=8.6 Hz, 1H), 7.69 (d, J=15.5 Hz, 1H), 7.94 (d, J=7.4 Hz, 1H), 8.05 (d, J=6.9 Hz, 1H), 9.18 (t, J=5.1 Hz, 1H), 12.99 (br, 1H).

PHARMACOLOGICAL EXPERIMENTS

(1) Protein Kinase C (PKC) Inhibitory Activity

Method for determining PKC activity:

The purification of PKC using rat's brain soluble fractions was carried out by a method of Kikkawa et al. (cf. Ushio Kikkawa, Yoshimi Takai, Ryoji Minakuchi, Sinichi Inohara and Yasutomi Nishizuka: The Journal of Biological Chemistry, vol. 257, No. 22, pp. 13341-13348 (1982)). PKC activity was determined by the transfer of radio activity from the [γ-³² P] adenosine triphosphate (ATP) to H1 histone derived from calf thymus in the presence of 20 mM Tris-HCl buffer (pH 7.5), H1 histone derived from calf thymus (200 μg/ml), 10 μM [γ-³² P]ATP, 5 mM magnesium acetate, 8 μg/ml phosphatidyl serine, 2 μg/ml diacylglycerol and 0.3 mM Ca²⁺. The test compound was dissolved in dimethylformamide, and the test compound solution was added to the assay system so that the final concentration thereof was adjusted to 0.8%. The reaction mixture was incubated at 30° C. for 30 minutes, and the reaction was quenched with 25% trichloroacetic acid. The acid-insoluble protein was collected on a nitrocellulose membrane by suction filtration. The radio activity of ³² P was determined by scintillation counter. The PKC inhibitory activity of the test compounds was expressed by IC₅₀, which is a concentration of the test compound to be required to reduce the PKC activity by 50%. The results are shown in Table 196.

Results:

                  TABLE 196                                                        ______________________________________                                         Test compound   PKC inhibitory activity (IC.sub.50, μM)                     ______________________________________                                         The compound of Example 71                                                                     0.8                                                              The compound of Example 88 0.1                                                 The compound of Example 89 0.3                                                 Tbe compound of Example 100 0.3                                                The compound of Example 160 0.6                                                The compound of Example 182 0.08                                               The compound of Example 192 0.8                                                The compound of Example 197 0.3                                              ______________________________________                                    

(2) Mouse Collagen Arthritis

Bovine II-type collagen (provided by Collagen Gijyutsu Kensyukai) (0.1%) was emulsified with Complete Fleund's adjuvant (CFA) (50%) (manufactured by DIFCO, Ltd.), and the emulsion thus obtained was injected intracutaneously to mice at the tail (primary sensitization). Three weeks later, bovine II-type collagen (0.1%) was injected intraperitoneally again to the mice (secondary sensitization). Three weeks later, the swelling of limbs of the mice was observed, and evaluated by four-degree as 0 to 3 each limb. The degree (0 to 3) each limb was added, and the results were used a score of the arthritis. That is, the maximum degree is 12 (degree 3×4 limb). The test compound was administered orally to the mice once a day, which started after two weeks from the primary sensitization.

In the mice treated with the compound of Example 182 at a dose of 30 to 50 mg/kg, the score of arthritis was significantly reduced in comparison with the control mice.

In the mice treated with the compounds of Example 160, 192 or 197 at a dose of 50 mg/kg, the score of arthritis was significantly reduced in comparison with the control mice.

(3) Mouse cGVHD (chromic Graft-versus-host disease model)

Female mice (DBA/2NCrj) were subjected to an operation of cervical vertebra dislocation, and the spleen was taken out to give the spleen cells preparation. The preparation were adjusted to 37.5×10⁷ cells/ml, and administered to the BDF1 female mice on the tail vein at a dose of 200 μl per a mouse. Two weeks later, the blood was collected in the absence of heparin, and anti-DNA antibody therein was determined by ELISA.

The compound of Example 182 was administered orally to the mice at a dose of 30 to 50 mg/kg once a day for two weeks, and the effect of the test compound on cGVHD was determined.

The amount of anti-DNA antibody in the blood was determined with OD₄₀₅. The amounts of anti-DNA antibody were 0.348±0.111 (mean±s.e.) in the control group, 0.255±0.062 (mean±s.e.) in the group treated with the compound of Example 182 at a dose of 30 mg/kg, and 0.094±0.026 (mean±s.e.) in the group treated with the compound of Example 182 at a dose of 50 mg/kg. From the results, it was proved that the compound of Example 182 reduced the anti-DNA antibody in the blood dose-dependently, compared with the control group.

Further, the compound of Example 100 was also administered orally to the mice at 30 mg/kg once a day for two weeks, and the effect of the compound on cGVHD was also determined.

The amount of anti-DNA antibody in the blood was determined with OD₄₀₅. The amounts of anti-DNA antibody were 0.258±0.084 (mean±s.e.) in the control group, and 0.177±0.061 (mean±s.e.) in the group treated with the compound of Example 100 at a dose of 30 mg/kg. From the results, it was proved that the compound of Example 100 reduced the anti-DNA antibody in the blood, compared with the control group.

(4) Rat Kidney Ischemic Re-perfusion Model

The right kidney of a SD male rat was taken out, and the left kidney artery was clumped, and then, re-perfused to give a kidney ischemic re-perfusion model. The effect of the compounds of Examples 71, 89 and 100 on the kidney ischemic re-perfusion model was estimated.

The compound of Example 71 was administered intravenously to the rat at a dose of 3 mg/kg 5 minutes before the ischemic. Twenty-four hours later, the blood was collected from the tail vein, and the amounts of creatine and urea nitrogen were determined. The amount of creatine in the blood was 2.19±0.21 (mean±s.e.) in the control group; 1.4±0.11 (mean±s.e.) in the group treated with the compound of Example 71, and the amount of urea nitrogen in the blood was 78.8±5.6 (mean s.e.) in the control group, and 54.1±5.0 (mean±s.e.) in the group treated with the compound of Example 71. That is, the compound of Example 71 significantly reduced the amounts of both of creatine and urea nitrogen, compared with the control group.

The compound of Example 89 was administered intravenously to the rat at a dose of 3 mg/kg 5 minutes before the ischemic and the re-perfusion. Forty-eight hours later, the blood was collected from the tail vein, and the amounts of creatine and urea nitrogen were determined. The amount of creatine in the blood was 4.31±0.53 (mean±s.e.) in the control group; 2.34±0.46 (mean±s.e.) in the group treated with the compound of Example 89, and the amount of urea nitrogen in the blood was 155.1±15.4 (mean±s.e.) in the control group, and 99.1±16.0 (mean±s.e.) in the group treated with the compound of Example 89. That is, the compound of Example 89 significantly reduced the amounts of both of creatine and urea nitrogen, compared with the control group.

The compound of Example 100 was administered orally to the rat at a dose of 30 mg/kg one hour before the ischemic. Forty-eight hours later, the blood was collected from the tail vein, and the amounts of creatine and urea nitrogen were determined. The amount of creatine in the blood was 2.48±0.59 (mean±s.e.) in the control group; 1.53±0.20 (mean±s.e.) in the group treated with the compound of Example 100, and the amount of urea nitrogen in the blood was 91.3±20.1 (mean±s.e.) in the control group, and 63.1±10.3 (mean±s.e.) in the group treated with the compound of Example 100. Thus, it is proved that the compound of Example 100 reduced the amounts of both of creatine and urea nitrogen, compared with the control group.

(5) Phorbol Ester (TPA)-induced Mouse Auricle Edema, Acanthosis Model

A 200 μg/ml phorbol ester (TPA) (10 μl) was applied to the one side to the ear of a female mouse (ICR). Twenty-four hours later, the thickness of the auricle of the mouse was determined with using a dialthickness gage, and the increase in the thickness of auricle was calculated. A test compound was dissolved in acetone, and the solution of a test compound was applied to the both sides of the ear 30 minutes before the application of TPA.

The compound of Example 88 was applied to the ear at a dose of 20 μl of 0.3% or 1% solution. The increase in the thickness of auricle in the control group is 215±40 μm (mean±s.e.) after 24 hours, while 87±53 μm (mean±s.e.) in the group treated with the compound of Example 88 in 0.3%, and 67±23 μm (mean±s.e.) in the group treated with the compound of Example 88 in 1%. Thus, the compound of Example 88 significantly reduced the increase in auricle thickness, compared with the control group.

(6) Mouse Atopic Dermatitis Model:

1% Trinitrobenzene (TNCB), (10 μl) was applied to each side of the ear of female mice (Balb/c), once every two days for 24 days. Twenty-four days later, the mice were grouped, and the auricle thickness of the mouse was determined by using a dial thickness gage, and the increase in the thickness of auricle was calculated. The compounds of Examples 88 and 89 were dissolved in acetone in a concentration of 1%. The compound of Example 182 was dissolved in a mixture of acetone:methanol in a concentration of 0.75%. Twenty-four days after the beginning of the experiment, the solution of a test compound was applied to each side of the ear 30 minutes before and after the application of TNCB, once a day for two weeks. The compound of Example 88 inhibited the increase in the auricle thickness by 25 to 30%, and the compounds of Examples 89 and 182 inhibited the increase in the auricle thickness by about 25%. Thus, it is proved that the compounds of the present invention is useful in the treatment of acanthosis induced by the application of TNCB. 

What is claimed is:
 1. A thiazole compound of the formula: ##STR1182## wherein T is a lower alkylene; u is 0 or 1;R¹ and R² are the same or different and are each a hydrogen atom or a lower alkyl, or both combine to form a group: --(CH₂)_(n) -- wherein n is 4 or 5 or to form a benzene ring which may optionally be substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino having optionally a lower alkyl substituent, or a halogen atom; R³ is a group of the formula: ##STR1183## wherein A is a lower alkylene; Z is O or S; s is 0 or 1; m is 1 or 2; R⁴ is a hydrogen atom or a lower alkanoyloxy-lower alkyl; R⁵ is/are the same or different and are each a member selected from (a) a hydrogen atom, (b) an alkyl having optionally a hydroxy substituent, (c) a halogen atom, (d) a group of the formula: --(O)_(t) --A--(CO)_(l) --NR⁷ R⁸ wherein t is 0 or 1, A is a lower alkylene, l is 0 or 1, and R⁷ and R⁸ are the same or different and are each a hydrogen atom or a lower alkyl, or both combine together with the nitrogen atom to which they bond to form a 5- to 7-membered saturated heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group being optionally substituted by a member selected from a group of the formula: --(A)_(l) --NR⁹ R¹⁰ wherein A and l are as defined above, and R⁹ and R¹⁰ are the same or different and are each a hydrogen atom or a lower alkyl, or both combine together with the nitrogen atom to which they bond to form a 5- to 7-membered saturated heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group having optionally a lower alkyl substituent, a lower alkyl having optionally a hydroxy substituent, a hydroxy group, and a lower alkanoyl; (e) a lower alkoxycarbonyl-lower alkyl, (f) a lower alkanoyloxy-lower alkyl, (g) a lower alkoxy having optionally a halogen substituent, (h) a halogen-substituted lower alkyl, (i) a carboxyl-substituted lower alkyl, (j) a lower alkoxycarbonyl, (k) a lower alkenyloxy, (l) a phenyl-lower alkoxy, (m) a cycloalkyloxy, (n) a phenyl, (o) a phenyloxy, (p) a hydroxy, (q) a lower alkylthio, (r) a lower alkenyl, or (s) an amino having optionally a lower alkyl substituent;R⁶ is a group of the formula:

    --CO--CH═CR.sup.11b --(CO).sub.p --R.sup.11a           ( 1)

or

    --CO--C.tbd.C--COR.sup.14 ;                                (2)

p is 0 or 1; R^(11b) is a hydrogen atom or a lower alkyl; R^(11a) is a hydroxy, a lower alkoxy, or a 5- to 10-membered, monocyclic or dicyclic, saturated or unsaturated heterocyclic group which contains 1 to 4 hetero atoms selected from a nitrogen, oxygen or sulfur atom as a ring member, said heterocyclic group having optionally 1 to 3 substituents selected from the group consisting of (i) a lower alkyl, (ii) a group of the formula: --(B)_(l) --NR¹² R¹³ wherein l is as defined above, B is --CO--A-- wherein A is as defined above, a carbonyl, or a lower alkylene, and R¹² and R¹³ are the same or different and are each a hydrogen atom, a lower alkyl, or a lower alkyl substituted by an amino having optionally a lower alkyl substituent, or both combine together with the nitrogen atom to which they bond to form a 5- to 12-membered saturated, monocyclic, dicyclic or spirocyclic heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group having optionally a substituent selected from a lower alkyl, a lower alkoxycarbonyl, a lower alkoxy-substituted lower alkyl, an amino having optionally a lower alkyl substituent, and a hydroxy-substituted lower alkyl), (iii) a lower alkoxycarbonyl, (iv) a hydroxy-substituted lower alkyl, (v) a pyridyl being optionally substituted by a lower alkyl having optionally a halogen substituent on the pyridine ring, (vi) a halogen-substituted lower alkyl, (vii) a lower alkoxy, (viii) a cycloalkyl, (ix) a hydroxy, (x) a tetrahydropyranyloxy-substituted lower alkyl, (xi) a pyrimidyl, (xii) a lower alkoxy-substituted lower alkyl, (xiii) a carboxyl, (xiv) a phenyl-lower alkoxy, (xv) a phenyl-lower alkyl having optionally a lower alkylenedioxy on the phenyl ring, (xvi) a lower alkanoyloxy, and (xvii) a piperidinyl having optionally a lower alkyl substituent on the piperidine ring; R¹⁴ is a hydroxy or a lower alkoxy; and when m is 1, the groups A and R⁵ may combine to form a group of the formula: ##STR1184## wherein R⁶ is as defined above, and r is 0, 1 or 2, or when m is 2, two R⁵ groups may combine to form a lower alkylenedioxy, a lower alkylene, or a group of the formula: --(CH₂)₂ --CONH--, or the groups R⁵ and R⁶ may combine to form a group of the formula: --CO--CH(R²⁸)--CH(R^(28'))--W-- wherein R²⁸ and R^(28') are a hydrogen atom or a carboxyl group, provided that both R²⁸ and R²⁸ are not simultaneously a carboxyl group, and W is --N(R^(29a))-- or ##STR1185## wherein R^(29a) is a hydrogen atom or a lower alkyl, R^(29b) is a lower alkyl, and X is as defined above, or a salt thereof.
 2. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² are the same or different and are each a hydrogen atom or a lower alkyl; and R³ is a group of the formula: ##STR1186## wherein A, R⁵, R⁶ and m are as defined in claim 1, and s is 0), or a salt thereof.
 3. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² are the same or different and are each a hydrogen atom or a lower alkyl; and R³ is a group of the formula: ##STR1187## wherein A, R⁵, R⁶ and m are as defined in claim 1, s is 1, and Z is O, or a salt thereof.
 4. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² are the same or different and are each a hydrogen atom or a lower alkyl; and R³ is a group of the formula: ##STR1188## wherein A, R⁵, R⁶ and m are as defined in claim 1, s is 1, and Z is S, or a salt thereof.
 5. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² combine to form a group: --(CH₂)_(n) -- wherein n is 4; and R³ is a group of the formula: ##STR1189## wherein A, R⁵, R⁶ and m are as defined in claim 1, and s is 0, or a salt thereof.
 6. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² combine to form a group: --(CH₂)_(n) -- wherein n is 4; and R³ is a group of the formula: ##STR1190## wherein A, R⁵, R⁶ and m are as defined in claim 1, s is 1, and Z is O; or a salt thereof.
 7. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 4); and R³ is a group of the formula: ##STR1191## wherein A, R⁵, R⁶ and m are as defined in claim 1, s is 1, and Z is S, or a salt thereof.
 8. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² combine to form a group: --(CH₂)_(n) -- wherein n is 5; and R³ is a group of the formula: ##STR1192## wherein A, R⁵, R⁶ and m are as defined in claim 1, and s is 0, or a salt thereof.
 9. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² combine to form a group: --(CH₂)_(n) -- wherein n is 5; and R³ is a group of the formula: ##STR1193## wherein A, R⁵, R⁶ and m are as defined in claim 1, s is 1, and Z is O, or a salt thereof.
 10. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² combine to form a group: --(CH₂)_(n) -- (n is 5); and R³ is a group of the formula: ##STR1194## wherein A, R⁵, R⁶ and m are as defined in claim 1, s is 1, and Z is S, or a salt thereof.
 11. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² combine to form a benzene ring which may optionally be substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino having optionally a lower alkyl substituent, or a halogen atom; and R³ is a group of the formula: ##STR1195## wherein A, R⁵, R⁶ and m are as defined in claim 1, and s is 0, or a salt thereof.
 12. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² combine to form a benzene ring which may optionally be substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino having optionally a lower alkyl substituent, or a halogen atom; and R³ is a group of the formula: ##STR1196## wherein A, R⁵, R⁶ and m are as defined in claim 1, s is 1, and Z is O, or a salt thereof.
 13. The thiazole compound according to claim 1, wherein u is 0; R¹ and R² combine to form a benzene ring which may optionally be substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino having optionally a lower alkyl substituent, or a halogen atom; and R³ is a group of the formula: ##STR1197## wherein A, R⁵, R⁶ and m are as defined in claim 1, s is 1, and Z is S, or a salt thereof.
 14. The thiazole compound according to claim 3, wherein R⁶ is a group of the formula: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) wherein R^(11a) is a hydroxy or a lower alkoxy, or a salt thereof.
 15. The thiazole compound according to claim 3, wherein R⁶ is a group of the formula: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) wherein p is 1, and R^(11a) is a 5- to 10-membered, monocyclic or dicyclic, saturated or unsaturated heterocyclic group which contains 1 to 4 hetero atoms selected from a nitrogen, oxygen or sulfur atom as a ring member, said heterocyclic group having optionally 1 to 3 substituents selected from the group consisting of (i) a lower alkyl, (ii) a group of the formula: --(B)_(l) --NR¹² R¹³ wherein B is --CO--A--, a carbonyl, or a lower alkylene, and R¹² and R¹³ are the same or different and are each a hydrogen atom, a lower alkyl, or a lower alkyl substituted by an amino having optionally a lower alkyl substituent, or both combine together with the nitrogen atom to which they bond to form a 5- to 12-membered saturated, monocyclic, dicyclic or spirocyclic heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group having optionally a substituent selected from a lower alkyl, a lower alkoxycarbonyl, a lower alkoxy-substituted lower alkyl, an amino having optionally a lower alkyl substituent, and a hydroxy-substituted lower alkyl), (iii) a lower alkoxycarbonyl, (iv) a hydroxy-substituted lower alkyl, (v) a pyridyl being optionally substituted by a lower alkyl having optionally a halogen substituent on the pyridine ring, (vi) a halogen-substituted lower alkyl, (vii) a lower alkoxy, (viii) a cycloalkyl, (ix) a hydroxy, (x) a tetrahydropyranyloxy-substituted lower alkyl, (xi) a pyrimidyl, (xii) a lower alkoxy-substituted lower alkyl, (xiii) a carboxyl, (xiv) a phenyl-lower alkoxy, (xv) a phenyl-lower alkyl having optionally a lower alkylenedioxy on the phenyl ring, (xvi) a lower alkanoyloxy, and (xvii) a piperidinyl having optionally a lower alkyl substituent on the piperidine ring, or a salt thereof.
 16. The thiazole compound according to claim 3, wherein R⁶ is a group of the formula: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) wherein p is 0, and R^(11a) is as defined in claim 15, or a salt thereof.
 17. The thiazole compound according to claim 3, wherein R⁶ is a group of the formula: --CO--C.tbd.C--COR¹⁴ or a salt thereof.
 18. The thiazole compound according to claim 12, wherein R⁶ is a group of the formula: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) wherein R^(11a) is a hydroxy or a lower alkoxy, or a salt thereof.
 19. The thiazole compound according to claim 12, wherein R⁶ is a group of the formula --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) wherein p is 1, and R^(11a) is a 5- to 10-membered, monocyclic or dicyclic, saturated or unsaturated heterocyclic group which contains 1 to 4 hetero atoms selected from a nitrogen, oxygen or sulfur atom as a ring member, said heterocyclic group having optionally 1 to 3 substituents selected from the group consisting of (i) a lower alkyl, (ii) a group of the formula: --(B)_(l) NR¹² R¹³ wherein l is O or 1, B is --CO--A-- wherein A is alkylene, a carbonyl, or a lower alkylene, and R¹² and R¹³ are the same or different and are each a hydrogen atom, a lower alkyl, or a lower alkyl substituted by an amino having optionally a lower alkyl substituent, or both combine together with the nitrogen atom to which they bond to form a 5- to 12-membered saturated, monocyclic, dicyclic or spirocyclic heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group having optionally a substituent selected from a lower alkyl, a lower alkoxycarbonyl, a lower alkoxy-substituted lower alkyl, an amino having optionally a lower alkyl substituent, and a hydroxy-substituted lower alkyl, (iii) a lower alkoxycarbonyl, (iv) a hydroxy-substituted lower alkyl, (v) a pyridyl being optionally substituted by a lower alkyl having optionally a halogen substituent on the pyridine ring, (vi) a halogen-substituted lower alkyl, (vii) a lower alkoxy, (viii) a cycloalkyl, (ix) a hydroxy, (x) a tetrahydropyranyloxy-substituted lower alkyl, (xi) a pyrimidyl, (xii) a lower alkoxy-substituted lower alkyl, (xiii) a carboxyl, (xiv) a phenyl-lower alkoxy, (xv) a phenyl-lower alkyl having optionally a lower alkylenedioxy on the phenyl ring, (xvi) a lower alkanoyloxy, and (xvii) a piperidinyl having optionally a lower alkyl substitutent on the piperidine ring, or a salt thereof.
 20. The thiazole compound according to claim 12, wherein R⁶ is a group of the formula: --CO--CH═CR^(11b) --(CO)_(p) --R^(11a) wherein p is 0, and R^(11a) is a 5- to 10-membered, monocyclic or dicyclic, saturated or unsaturated heterocyclic group which contains 1 to 4 hetero atoms selected from a nitrogen, oxygen or sulfur atom as a ring member, said heterocyclic group having optionally 1 to 3 substituents selected from the group consisting of (i) a lower alkyl, (ii) a group of the formula: --(B)_(l) NR¹² R¹³ wherein l is O or 1, B is --CO--A-- wherein A is alkylene, a carbonyl, or a lower alkylene, and R¹² and R¹³ are the same or different and are each a hydrogen atom, a lower alkyl, or a lower alkyl substituted by art amino having optionally a lower alkyl substituent, or both combine together with the nitrogen atom to which they bond to form a 5- to 12-membered saturated, monocyclic, dicyclic or spirocyclic heterocyclic group which may be intervened with a nitrogen or oxygen atom, said heterocyclic group having optionally a substituent selected from a lower alkyl, a lower alkoxycarbonyl, a lower alkoxy-substituted lower alkyl, an amino having optionally a lower alkyl substituent, and a hydroxy-substituted lower alkyl, (iii) a lower alkoxycarbonyl, (iv) a hydroxy-substituted lower alkyl, (v) a pyridyl being optionally substituted by a lower alkyl having optionally a halogen substituent on the pyridine ring, (vi) a halogen-substituted lower alkyl, (vii) a lower alkoxy, (viii) a cycloalkyl, (ix) a hydroxy, (x) a tetrahydropyranyloxy-substituted lower alkyl, (xi) a pyrimidyl, (xii) a lower alkoxy-substituted lower alkyl, (xiii) a carboxyl, (xiv) a phenyl-lower alkoxy, (xv) a phenyl-lower alkyl having optionally a lower alkylenedioxy on the phenyl ring, (xvi) a lower alkanoyloxy, and (xvii) a piperidinyl having optionally a lower alkyl substitutent on the piperidine ring, or a salt thereof.
 21. The thiazole compound according to claim 12, wherein R⁶ is a group of the formula: --CO--C.tbd.C--COR¹⁴ or a salt thereof.
 22. The thiazole compound according to claim 1, wherein u is 1; R¹ and R² are the same or different and are each a hydrogen atom or a lower alkyl; and R³ is a group of the formula: ##STR1198## wherein A, Z, s, R⁵, R⁶ and m are as defined in claim 1, or a salt thereof.
 23. The thiazole compound according to claim 1, wherein u is 1; R¹ and R² combine to form a group: --(CH₂)_(n) -- wherein n is 4; and R³ is a group of the formula: ##STR1199## wherein A, Z, s, R⁵, R⁶ and m are as defined in claim 1, or a salt thereof.
 24. The thiazole compound according to claim 1, wherein u is 1; R¹ and R² combine to form a group: --(CH₂)_(n) -- wherein n is 5; and R³ is a group of the formula: ##STR1200## wherein A, Z, s, R⁵, R⁶ and m are as defined in claim 1, or a salt thereof.
 25. The thiazole compound according to claim 1, wherein u is 1; R¹ and R² combine to form a benzene ring which may optionally be substituted by a member selected from a lower alkyl, a lower alkoxy, a nitro, an amino having optionally a lower alkyl substituent, or a halogen atom; and R³ is a group of the formula: ##STR1201## wherein A, Z, s, R⁵, R⁶ and m are as defined in claim 1, or a salt thereof.
 26. The thiazole compound according to any one of claims 2, 5-7, 8-10, 11, 13 and 22-25, wherein the heterocyclic group for R^(11a) is a member selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholino, 1-azacyclooctyl, homopiperazinyl, homomorpholino, 1,4-diazabicyclo[4.3.0]nonyl, 1,4-diazabicyclo[4.4.0]decyl, pyridyl, 1,2,5,6-tetrahydropyridyl, thienyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, 1,3,4-triazolyl, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, pyrrolyl, pyrrolinyl, carbostyril, 1,3-dioxolanyl, thiomorpholino, 3,4-dihydrocarbostyril, 1,2,3,4-tetrahydroquinolyl, 2,3,4,5-tetrahydrofuryl, indolyl, isoindolyl, 3H-indolyl, indolinyl, indolidinyl, indazolyl, benzimidazolyl, benzoxazolyl, imidazolinyl, imidazolidinyl, isoquinolyl, naphthylidinyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, thienyl, imidazolyl, pyrazolidinyl, benzofuryl, 2,3-dihydrobenzo[b]furyl, benzothienyl, tetrahydropyranyl, 4H-chromenyl, 1H-indazolyl, isoindolinyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, pyranyl, pyrazolidinyl, 2-pyrazolinyl, quinuclidinyl, 1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, 1,4-dithianaphthalenyl, 2,5-dihydrofurano[3,4-c]pyridyl, 2,3,4,5,6,7-hexahydro-1H-azepinyl, 1,2,3,4,5,6,7,8-octahydroazocinyl, 1,2,3,4,5,6-hexahydrooxepinyl, 1,3-dioxolanyl, 3,4,5,6-tetrahydro-2H-pyranyl, and 5,6-dihydro-2H-pyranyl.
 27. A thiazole compound selected from the group consisting of(1) 2-{(3-methoxy-4-(3-(4-(4-methyl-1-homopiperazinyl)-1-piperidinylcarbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, (2) 2-{(2-isopropyl-4-(3-(4-(4-methyl-1-piperazinyl)-1-piperidinylcarbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, (3) 2-{(2-methoxy-4-(3-(2-(4-methyl-1-piperazinyl)-methyl-4-morpholinocarbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, (4) 2-{(2-ethoxy-4-(3-(4-(4-methyl-1-piperazinyl)-1-piperidinylcarbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, (5) 2-{(3-methyl-4-(3-(4-(4-methyl-1-homopiperazinyl)-1-piperidinylcarbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, (6) 2-{(3-methoxy-6-ethyl-4-(3-(4-(4-methyl-1-homopiperazinyl)-1-piperidinylcarbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, (7) 2-{(3-methoxy-6-ethyl-4-(3-(4-methyl-1-piperazinyl)acryloyl)-phenoxy)methylcarbonylamino}benzothiazole, (8) 2-{(2-trifluoromethyl-4-(3-(4-hydroxy-1-piperazinyl)acryloyl)-phenoxy)methylcarbonylamino}benzothiazole, (9) 2-{(2-fluoro-4-(3-(2-(4-methyl-1-piperazinyl)methyl-4-morpholino-carbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, (10) 2-{(2-methoxy-4-(3-(4-(4-methyl-1-piperazinyl)-1-piperidinylcarbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, (11) 2-{(2,3-dimethyl-4-(3-(4-(4-methyl-1-homopiperazinyl)-1-piperidinylcarbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, (12) 2-{(3-methoxy-4-(3-(4-(3,4-dimethyl-1-piperazinyl)-1-piperidinylcarbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, (13) 2-{(3-methoxy-6-isopropyl-4-(3-(4-methyl-1-piperazinyl)-carbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, (14) 2-{(2-methoxy-4-(3-(4-(4-methyl-1-homopiperazinyl)-1-piperidinylcarbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, and (15) 2-{(2-n-butyl-4-(3-(4-(4-methyl-1-homopiperazinyl)-1-piperidinylcarbonyl)acryloyl)phenoxy)methylcarbonylamino}benzothiazole, or a salt thereof.
 28. A protein kinase C inhibitor composition which comprises as an active ingredient a thiazole compound or a salt thereof as set forth in claim
 1. 29. A process for preparing a thiazole compound as set forth in claim 1, which comprises the following steps of(a) reacting a compound of the formula (2): ##STR1202## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1, with a compound of the formula (3): ##STR1203## wherein R^(11b) is the same as defined in claim 1, or a compound of the formula (4): ##STR1204## wherein R¹⁵ is a group: --CH═C(R^(11b))(COR¹⁶) wherein R^(11b) is the same as defined in claim 1, and R¹⁶ is a hydroxy group or a lower alkoxy group, or a group: --C.tbd.C--COR¹⁴ wherein R¹⁴ is the same as defined in claim 1, and X is a halogen atom, to give a compound of the formula (1a): ##STR1205## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1, and R¹⁵ is the same as defined above; (b) reacting a compound of the formula (1b): ##STR1206## wherein R¹, R², R⁴, R⁵, R^(11b), Z, m, s, T, u and A are the same as defined in claim 1, with a compoud of the formula (5):

    R.sup.17 H                                                 (5)

wherein R¹⁷ is the heterocyclic groups as defined for R^(11a) of claim 1 but having at least one ##STR1207## in the heterocyclic nucleus, to give a compoud of the formula (1c): ##STR1208## wherein R¹, R², R⁴, R⁵, R^(11b), Z, m, s, T, u and A are the same as defined in claim 1, and R¹⁷ is the same as defined above; (c) reacting a compound of the formula (10): ##STR1209## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1, R¹⁸ is a lower alkoxy group, with a compound of the formula (12): ##STR1210## wherein R¹⁶ is the same as defined above, to give a compound of the formula (1d): ##STR1211## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1 and R¹⁶ is the same as defined above; (d) reacting a compound of the formula (10): ##STR1212## wherein R¹, R², R⁴, R⁵, Z, m, S, T, u and A are the same as defined in claim 1, and R¹⁸ is the same as defined above, with a compound of the formula (20):

    R.sup.22 CHO                                               (20)

wherein R²² is a 5- to 10-membered, saturated or unsaturated heteromonocyclic or heterobicyclic group said heteromonocyclic or heterobicyclic group optionally having 1 to 3 substituents selected from (i) a lower alkyl group; (ii) a group: --(B)_(l) NR¹² R¹³, wherein l is O or 1, B is a group: --CO--A-- (wherein A is alkylene), a carbonyl group or a lower alkylene group, R¹² and R¹³ are the same or different, and each are a hydrogen atom, a lower alkyl group, an amino-substituted lower alkyl group having optionally a lower alkyl substituent, or both combine together with the adjacent nitrogen atom to which they bond to form a 5- to 12-membered saturated heteromonocyclic, heterobicyclic or hetero-sprio ring with or without being intervened with another nitrogen atom or an oxygen atom, said heterocyclic group may optionally have a substituent selected from a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy-substituted lower alkyl group, an amino group having optionally a lower alkyl substituent and a hydroxy-substituted lower alkyl group); (iii) a lower alkoxycarbonyl group; (iv) a hydroxy-substituted lower alkyl group; (v) a pyridyl group being optionally substituted by a lower alkyl group having optionally a halogen substituent on the pyridine ring; (vi) a halogen-substituted lower alkyl group; (vii) a lower alkoxy group; (viii) a cycloalkyl group; (ix) a hydroxy group; (x) a tetrahydropyranyloxy-substituted lower alkyl group; (xi) a pyrimidyl group; (xii) a lower alkoxy-substituted lower alkyl group; (xiii) a carboxyl group; (xiv) a phenyl-lower alkoxy group; (xv) a phenyl-lower alkyl group having optionally a lower alkylenedioxy substituent on the phenyl ring; (xvi) a lower alkanoyloxy group; and (xvii) a piperidinyl group having optionally a lower alkyl substituent on the piperidine ring, to give a compound of the formula (1h): ##STR1213## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1, and R¹⁸ and R²² are the same as defined above; (e) converting, a compound of the formula (11): ##STR1214## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1, and R²⁰ is a lower alkoxy group, into a compound of the formula (1d'): ##STR1215## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1, and R^(16a) is a lower alkoxy group, in the presence of a basic compound, optionally followed by converting the compound (1d') into a compound of the formula (1e): ##STR1216## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1, in the presence of an acid or a basic compound; (f) converting a compound of the formula (11): ##STR1217## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1, and R²⁰ is a lower alkoxy group, into a compound of the formula (1f): ##STR1218## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u, and A are the same as defined in claim 1, and R²⁰ is the same as defined above, in the presence of an oxidizing agent, optionally followed by converting, the compound (1f) into a compound of the formula (1g): ##STR1219## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1, in the presence of an acid or a basic compound; (g) reacting a compound of the formula (19): ##STR1220## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1, and R²¹ is a phenyl group, with a compound of the formula (20):

    R.sup.22 CHO                                               (20)

wherein R²² is the same as defined above, to give a compound of the formula (1h): ##STR1221## wherein R¹, R², R⁴, R⁵, Z, m, s, T, u and A are the same as defined in claim 1, and R²² is the same as defined above; (h) reacting a compound of the formula (23): ##STR1222## wherein R³ is the same as defined in claim 1, with a compound of the formula (24): ##STR1223## wherein R¹, R², R⁴, T and u are the same as defined in claim 1, to give a compound of the formula (1): ##STR1224## wherein R¹, R², R³, R⁴, T and u are the same as defined in claim 1; (i) reacting a compound of the formula (19a): ##STR1225## wherein T, u, R¹, R², R⁴, Z, R⁵ and m are the same as defined in claim 1, and R²¹ is the same as defined above, and A' is a lower alkylene group, with a compound of the formula (44):

    OHC.COOH                                                   (44)

to give a compound of the formula (1q): ##STR1226## wherein T, u, R¹, R², R⁴, Z, R⁵ and m are the same as defined in claim 1 and A' is a lower alkylene group. 